Stereochemical models for the enantiocontrolled construction of fully functionalized C rings via intramolecular aldolization in advanced precursors to paclitaxel

Article abstract of DOI:10.1021/jo981749j

Six transition-state models for intramolecular aldol C-ring annulation in suitably substituted bicyclo-[6.2.1]undecanones have been defined. The first consideration is the inherent conformational flexibility of the nine- membered ketonic ring which does not limit effective deprotonation to a single C-8 epimer. When the oxygen substituents at C-4 and C-5 are not covalently linked, the configuration at C-5 defines the stereochemical course of the ring closure, with only the β series being amenable to the proper elaboration of paclitaxel. When C-4 and C-5 are incorporated into a 1,3- dioxane ring instead, the principal stereocontrol element is translocated into the aryl-substituted carbon of the cyclic acetal. To the extent that the Ar group remains equatorially disposed, then proper aldolization will materialize in only one of the four possible diastereomers. Experimental tests that are provided for three of the models are shown to conform to expectations. This analysis of the origin of stereoselectivity has, for the first time, defined the scope and limitations associated with C-ring closure by means of the aldol protocol.

Full text of DOI:10.1021/jo981749j

J . Org. Chem. 1998, 63, 8491-8509
8491
Ster eoch em ica l Mod els for th e En a n tiocon tr olled Con str u ction of
F u lly F u n ction a lized C Rin gs via In tr a m olecu la r Ald oliza tion in
Ad va n ced P r ecu r sor s to P a clita xel
Leo A. Paquette,* Qingbei Zeng, Hon-Chung Tsui, and J effrey N. J ohnston
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received August 26, 1998
Six transition-state models for intramolecular aldol C-ring annulation in suitably substituted bicyclo-
[6.2.1]undecanones have been defined. The first consideration is the inherent conformational
flexibility of the nine-membered ketonic ring which does not limit effective deprotonation to a single
C-8 epimer. When the oxygen substituents at C-4 and C-5 are not covalently linked, the
configuration at C-5 defines the stereochemical course of the ring closure, with only the â series
being amenable to the proper elaboration of paclitaxel. When C-4 and C-5 are incorporated into a
1,3-dioxane ring instead, the principal stereocontrol element is translocated into the aryl-substituted
carbon of the cyclic acetal. To the extent that the Ar group remains equatorially disposed, then
proper aldolization will materialize in only one of the four possible diastereomers. Experimental
tests that are provided for three of the models are shown to conform to expectations. This analysis
of the origin of stereoselectivity has, for the first time, defined the scope and limitations associated
with C-ring closure by means of the aldol protocol.
Of the five successfully completed total syntheses of
paclitaxel (1),1-5 two rely on an intramolecular aldol
reaction to construct ring C and establish proper config-
uration at C-7 and C-8 (Scheme 1).4,5a The two research
groups involved have recently addressed in explicit terms
the fact that the transformation of 2 into 3 as well as of
4 into 5 requires that the methyl substituent positioned
at the enolizable center be â-oriented.4-6 Only when this
condition is met is proper orbital overlap for proton
abstraction realized. In contrast, 6 is inert to aldol
closure and even to base-catalyzed H/D exchange because
the relevant proton is rigidly positioned orthogonal to the
carbonyl π-bond.
(1) (a) Holton, R. A.; Somoza, C.; Kim, H.-B.; Liang, F.; Biediger, R.
J .; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.;
Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile,
L. N.; Liu, J . H. J . Am. Chem. Soc. 1994, 116, 1597. (b) Holton, R. A.;
Kim, H.-B.; Somoza, C.; Liang, F.; Biediger, R. J .; Boatman, P. D.;
Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.;
Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J . H. J .
Am. Chem. Soc. 1994, 116, 1599.
(2) (a) Nicolaou, K. C.; Yang, Z.; Liu, J . J .; Ueno, H.; Nantermet, P.
G.; Guy, R. K.; Claiborne, C. F.; Renaud, J .; Couladouros, E. A.;
Paulvannan, K.; Sorensen, E. J . Nature 1994, 367, 630. (b) Nicolaou,
K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K.; Couladouros, E. A.;
Sorensen, E. J . J . Am. Chem. Soc. 1995, 117, 624. (c) Nicolaou, K. C.;
Liu, J .-J .; Yang, Z.; Ueno, H.; Sorensen, E. J .; Claiborne, C. F.; Guy,
R. K.; Hwang, C.-K.; Nakada, M.; Nantermet, P. G. J . Am. Chem. Soc.
1995, 117, 634. (d) Nicolaou, K. C.; Yang, Z.; Liu, J .-J .; Nantermet, P.
G.; Claiborne, C. F.; Renaud, J .; Guy, R. K.; Shibayama, K. J . Am.
Chem. Soc. 1995, 117, 645. (e) Nicolaou, K. C.; Ueno, H.; Liu, J .-J .;
Nantermet, P. G.; Yang, Z.; Renaud, J .; Paulvannan, K.; Chadha, R.
J . Am. Chem. Soc. 1995, 117, 653.
(3) (a) Masters, J . J .; Link, J . T.; Snyder, L. B.; Young, W. B.;
Danishefsky, S. J . Angew. Chem., Int. Ed. Engl. 1995, 34, 1723. (b)
Danishefsky, S. J .; Masters, J . J .; Young, W. B.; Link, J . T.; Snyder,
L. B.; Magee, T. V.; J ung, D. K.; Isaacs, R. C. A.; Bornmann, W. G.;
Alaimo, C. A.; Coburn, C. A.; Di Grandi, M. J . J . Am. Chem. Soc. 1996,
118, 2843.
(4) (a) Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P.
E.; Glass, T. E.; Gra¨nicher, C.; Houze, J . B.; J a¨nichen, J .; Lee, D.;
Marquess, D. G.; McGrane, P. L.; Meng, W.; Mucciaro, T. P.; Mu¨hle-
bach, M.; Natchus, M. G.; Paulsen, H.; Rawlins, D. B.; Satkofsky, J .;
Shuker, A. J .; Sutton, J . C.; Taylor, R. E.; Tomooka, K. J . Am. Chem.
Soc. 1997, 119, 2755. (b) Wender, P. A.; Badham, N. F.; Conway, S.
P.; Floreancig, P. E.; Glass, T. E.; Houze, J . B.; Krauss, N. E.; Lee, D.;
Marquess, D. G.; McGrane, P. L.; Meng, W.; Natchus, M. G.; Shuker,
A. J .; Sutton, J . C.; Taylor, R. E. J . Am. Chem. Soc. 1997, 119, 2757.
(5) (a) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Sakoh, H.; Tani, Y.;
Hasegawa, M.; Saitoh, K. Proc. J pn. Acad. 1997, 73B, 95. (b) Stork,
G.; Manabe, K.; Liu, L. J . Am. Chem. Soc. 1998, 120, 1337.
Our group has also approached the paclitaxel problem
by taking advantage of a comparable aldol ring closure.
The major distinction is that this process is initiated by
us within appropriately functionalized bicyclo[6.2.1]-
undecanones prior to bridge migration via R-ketol re-
arrangement. The conversion of 7 to 8, and subsequently
via 9 to 10, is illustrative of the tactic (Scheme 2).7 We
were guided in this venture by early knowledge of the
fact that bicyclic ketones such as 7 and higher tricyclic
congeners thereof are more conformationally flexible than
2 and 4.8 Although atropisomerization has been observed
(6) For an earlier discussion of the preferred ground-state conforma-
tion of trans-fused B/C taxoids, see: (a) Swindell, C. S.; de Solms, S.
J . Tetrahedron Lett. 1987, 28, 3801. (b) Wender, P. A.; Ihle, N. C.
Tetrahedron Lett. 1987, 28, 2451.
(7) Paquette, L. A.; Montgomery, F. J .; Wang, T.-Z. J . Org. Chem.
1995, 60, 7857.
(8) (a) Paquette, L. A.; Pegg, N. A.; Toops, D.; Maynard, G. D.;
Rogers, R. D. J . Am. Chem. Soc. 1990, 112, 277. (b) Pegg, N. A.;
Paquette, L. A. J . Org. Chem. 1991, 56, 2461. (c) Paquette, L. A.; Zhao,
M. J . Am. Chem. Soc. 1993, 115, 354. (d) Paquette, L. A.; Elmore, S.
W.; Combrink, K. D.; Hickey, E. R.; Rogers, R. D. Helv. Chim. Acta
1992, 75, 1755. (e) Paquette, L. A.; Combrink, K. D.; Elmore, S. W.;
Zhao, M. Helv. Chim. Acta 1992, 75, 1772.
10.1021/jo981749j CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/27/1998

8492 J . Org. Chem., Vol. 63, No. 23, 1998
Paquette et al.
Con for m a tion a l An a lysis
Sch em e 1
Construction of the oxetane ring in paclitaxel can
ultimately be approached from two directions. If OR3 is
designed to serve as the nucleofugal substituent, this
functionality must originally reside on the R-surface in
order to allow for anticipated configurational inversion
during the SN2 displacement step. The stereochemical
arrangement defined by this precondition is found in
structural formula A1 in Figure 1. If, on the other hand,
OR2 is predetermined to be the leaving group, OR3 must
already be predisposed â as in B1. For simplification
purposes, OR2 and OR3 are initially considered to be
structurally independent of each other. The low-energy
conformations anticipated to be operational during in-
tramolecular aldol cyclization within each of these dia-
stereomers are depicted as A2 and B2, respectively. In
these illustrations, the major controller of conformational
bias is the equatorial orientation of two of the three
groups at C-4 and C-5. Although enolate geometry is
comparable in both series, the nine-membered nature of
the B ring is, as previously indicated, sufficiently flexible
to accommodate the adoption of conformers A2 and B2.9
As a consequence, the precise relationship imposed
between the enolate double bond and the aldehyde
functionality becomes paramount. Thus, the ring closure
of A2 to A3 necessarily orients the C-7 hydroxyl and C-8
methyl groups R while projecting the C-9 carbonyl in a
downward direction. On the other hand, the electrophilic
aldehyde center in B2 is constrained to approaching the
opposite face of the enolate. Under these circumstances,
C-C bond formation proceeds with proper installation
of the stereocenters at C-7 and C-8, along with upward
orientation of the C-9 keto group (see B3 and B4). A 1,3-
diaxial interaction is noted to develop along the A
reaction trajectory. On the basis of this analysis, we
conclude that the stereochemical disposition of the oxy-
genated substituents at C-4 and C-5 as in B1 is a very
important consideration for aldolization favorable to the
acquisition of paclitaxel. The successful conversion of 7
to 8 exemplifies the anticipated diastereoselectivity.
Other examples in support of this analysis are provided
below.
We next consider the option of achieving hydroxyl
protection by conversion to a benzylidene acetal (see
section B of Figure 1). With the introduction of a new
stereocenter (labeled with an asterisk (*)), it becomes
additionally necessary to specify the configuration of the
Ar substituent. Our evaluation of the stereochemically
induced interrelationship of C-5 and C* on conformation
has once again led us to the conclusion that aldol-related
matters should be manageable. Two conditions are
considered to be fundamental and intrinsic to the 1,3-
dioxane subunit. The first is the expectation that steric
interactions will be minimized upon adoption of a chair
geometry. Additionally, equatorial projection of the Ar
substituent should be favored. Therefore, structures C2-
F 2 presumably experience the lowest level of con-
formational destabilization in the four possible dia-
stereomers.
in systems exemplified by 11 and 12, warming in THF
is adequate to achieve conformational interconversion in
most cases. The significance of this heightened flexibility
gains importance when deprotonation of ketones such as
7 is being considered. As a direct consequence of the
molecular motion attainable within 7 and analogues
thereof, no difficulty arises in the transient population
of conformers conducive to proper overlap of the C-8
proton for enolate generation. These considerations hold
importance because they allow attention to be redirected
to other central stereochemical factors associated with
the intramolecular aldol process. These issues gain
particular significance when the confluence of functional-
ity present in the side chain reaches the heightened level
found in 7. Thus, successful aldol ring closure will
materialize only if the enolate anion adds to the aldehyde
carbonyl at a rate faster than unwanted â-elimination
of p-methoxybenzyl alcohol. Additionally, the nucleo-
philic C-8 center must be conjoined to the C-7 electro-
philic site from the appropriate π-surface at each termi-
nus. Such an event must not be forced to operate against
prevailing low-energy conformational preferences that
would dictate otherwise. The minimization of these risk
factors is directly relevant to the success of this protocol.
In this paper, we document the issues considered to be
critical to the successful deployment of the aldol process
in paclitaxel C-ring construction when beginning with 7
and related structural congeners.
These restrictions support the proposition that con-
formers C2 and D2 should experience complementary
interactions that are expected to favor bonding of the
(9) For the dynamic behavior of diastereomeric trans-∆9,10-tricyclo-
[9.3.1.03.8]pentadecenes, consult ref 8c and the following: Paquette,
L. A.; Zhao, M. J . Am. Chem. Soc. 1998, 120, 5953.

C Ring Construction via Intramolecular Aldolization
J . Org. Chem., Vol. 63, No. 23, 1998 8493
Sch em e 2
aldehyde to the si face of the enolate anion, resulting in
incorrect installation of C-7 and C-8 stereochemistry.
Thus, matching of the configuration at C-5 and C* in
either the R sense (see C1) or in a dual â direction (as in
D1) has the untoward consequence of constraining the
aldol process to unwanted stereoinduction pathways.
Likewise, the arrangement of the key substituents as in
F 1 is clearly not in a reinforcing relationship and is
unquestionably unattractive on that basis. In contrast,
the anti relationship present in E1 contributes simulta-
neously to a selectivity for bonding to the re face of the
enolate (see E2), this diastereomeric relationship con-
tributing to the preferential formation of E4. By inspec-
tion, therefore, it is evident that any deployment of an
acetal protecting group for the hydroxyls resident at C-4
and C-5 must accord due consideration to a number of
configurational and conformational factors.
refluxing methanol12 gives rise to aldehyde 20 with
destruction of this stereogenic center. The stringent
requirement that the homologation of 20 to 21 proceed
with Z stereoselectivity in order to guarantee the orien-
tation of this side chain later in 24 was ideally met by
Wittig condensation with (iodomethylene)triphenylphos-
phorane.13 In agreement with this assignment, the
coupling constant observed for the vinylic protons located
in the iodoethylene moiety of 21 is 8.9 Hz.
The vinyl anion corresponding to 21 could be generated
by treatment with n-butyllithium in ether at -78 °C and
added to norbornanone 22.8d As is customary for these
systems, the presence of an apical syn methyl group
directs nucleophilic attack to the endo surface. This more
sterically congested reaction trajectory is reflected in the
observation that the desired 1,2-addition proceeded at a
reasonable rate only when room temperature conditions
were approached. Notwithstanding, the yield of 23 was
excellent (Scheme 5). Exposure of 23 to potassium
hexamethyldisilazide and 18-crown-6 in THF at low
temperatures (-78 °C f -60 °C) promoted anionic oxy-
Cope rearrangement14 via an endo-chair transition state.8a
This process occurs readily to generate an enolate anion
regiospecifically. The presence of the crown ether se-
questers the potassium ion, thereby significantly enhanc-
ing the reactivity of the enolate intermediate to the point
where C-alkylation with methyl iodide takes place rap-
idly at -78 °C. Under these conditions, ketone 24 is
formed uniquely in 80% overall isolated yield. Detailed
NOE studies performed on this product revealed the
absence of interactions involving the newly introduced
CH3 group and the vinylic proton of the bridgehead,15
thereby requiring an R-orientation for this substit-
uent.
Su p p or t for th e Con for m a tion a l Mod els
On the basis of the preceding analysis, the stereochem-
ical features associated with B1 are seen to be particu-
larly conducive to intramolecular aldolization with the
proper facial selectivity when R2 and R3 are not part of a
dioxane ring. This working hypothesis has been sub-
stantiated on the basis of three case studies. Previous
disclosure has been made of the stereoselective cycliza-
tion of 7 to 8 in 85% yield,7 and of the unidirectional
conversion of 13 into 14 (Scheme 3).10 The third example
is represented by the transformation of 27 into 29.
Arrival at 27 requires that access first be gained to the
Z vinyl iodide 21. To this end, the known diol 157 was
chemoselectively protected in turn at its primary (as in
16) and secondary hydroxyl groups to give 17 (Scheme
4). Heating 17 in ethanol containing pyridinium p-
toluenesulfonate resulted in near-quantitative conversion
to 18, thereby making possible the formation of primary
iodide 19 in conventional fashion.11 The production of
19 as an anomeric mixture is of no long-range conse-
quence since its ensuing reductive cleavage with zinc in
The low-temperature conditions utilized for the pro-
duction of 24 were expected to favor delivery of the
carbonyl-up atropisomer as shown. Proper documenta-
(12) (a) Gallos, J . K.; Goga, E. G.; Koumbis, A. E. J . Chem. Soc.,
Perkin Trans. 1 1994, 613. (b) Gallos, J . K.; Koftis, T. V.; Koumbis, A.
E. J . Chem. Soc., Perkin Trans. 1 1994, 611.
(13) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
(14) (a) Paquette, L. A. Tetrahedron 1997, 53, 13971. (b) Paquette,
L. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609.
(10) Paquette, L. A.; Bailey, S. J . Org. Chem. 1995, 60, 7849.
(11) (a) Garegg, P. J .; Samulesson, B. J . Chem. Soc., Perkin Trans.
(15) The proximity of the bridgehead vinylic proton to the syn apical
1
1980, 2866. (b) Corbett, D. F.; Dean, D. K.; Robinson, S. R.
methyl group was clearly evidenced by
enhancement at the 5.9% level.
a strong mutual signal
Tetrahedron Lett. 1993, 34, 1525.

8494 J . Org. Chem., Vol. 63, No. 23, 1998
Paquette et al.
F igu r e 1. Putative low-energy conformations associated with intramolecular aldol cyclization of stereochemically varied C-ring
precursors to paclitaxel.
tion of this conclusion comes from two directions. First,
regioselective dihydroxylation of 24 followed by silylation
of the resulting secondary OH functionality gave rise to
25 without any evidence for transannular hemiketaliza-
tion. This reluctance to undergo intramolecular bonding
across the nine-membered ring is generally encountered
when the carbonyl is oriented up because of the reduced
flexibility of this conformer.7,8 More revealing yet was
the discovery that the charge-accelerated [3,3] sigma-
tropic rearrangement of 23 at 0 °C followed by low-
temperature methylation furnished only the carbonyl-
down ketone 31 (Scheme 6). To define the direction of

C Ring Construction via Intramolecular Aldolization
J . Org. Chem., Vol. 63, No. 23, 1998 8495
Sch em e 3
With the stereochemical features of 25 secure,16 the
planned elaboration of ring C could now be given con-
sideration. Hydroboration-oxidation of the terminal
vinyl group in 25 was accomplished with thexylborane
in order to maximize the level of primary carbinol 26
produced. Recourse to Swern oxidation subsequently
afforded 27 without complication, thereby setting the
stage for intramolecular aldol ring closure. Initial ex-
periments involving the use of sodium hydroxide in a
mixed methanol/THF solvent system at -5 °C or of
titanium tetraisopropoxide in THF at room temperature
were met with rapid â-elimination of p-methoxybenzyl
alcohol and slower ring closure to give 28 in 65-79%
yield. The â-orientation of the hydroxyl and angular
methyl substituents in this tricyclic product was cor-
roborated by definitive NOE measurements.17 Al-
though the stereochemical outcome of the intramo-
lecular aldolization conformed to expectation, permuta-
tions in the reaction conditions were necessary in order
to demonstrate feasibility without loss of important
oxygenated functionality. Our efforts were soon re-
warded with the discovery that recourse to lithium
hydroxide in THF at -12 °C was capable of delivering
29. As a consequence of overlapping proton signals in
Sch em e 4
1
the high-field H NMR spectrum of 29, the configurations
at C-7 and C-8 could not be rigorously defined. Therefore,
the benzoate 30 was prepared. At this point, it was an
easy matter to confirm by NOE methods that the features
present in paclitaxel were resident in this product, as
depicted in the inset. With the completion of this phase
of our investigation, little doubt remained that the
(16) The distinctive chemical shift of the C-8 methyl in this advanced
intermediate provided an opportunity for added verification of the
R-orientation of this substituent as shown below:
entry of the methyl group, 31 was reduced with lithium
aluminum hydride and the R-alcohol was protected as
the SEM ether. These chemical transformations posi-
tioned H-8 in a unique region of the high-field NMR
spectrum. It was then possible to establish stereochem-
istry convincingly by NOE methods. Two key observa-
tions are indicated directly on the structural formula.
When 31 was subjected to osmylation, hemiacetal 33 was
formed, in line with expectations.
(17) Among the more definitive signal enhancements are those
shown below:
The remarkable atropisomeric control associated with
the oxy-Cope rearrangement of 23 suggests that while
enolate anion 34 is generated under kinetic control and
is capable of retaining its geometry at or below -60 °C,
strain factors facilitate its conformational inversion to
produce 35 at more elevated temperatures. Both of these
reactive intermediates exhibit a proclivity for the capture
of methyl iodide from that surface anti to the side chain
at C-7.

8496 J . Org. Chem., Vol. 63, No. 23, 1998
Paquette et al.
Sch em e 5
B1-B4 transition model in Figure 1 is particularly
conducive to paclitaxel synthesis.
to positionally specific silylation and oxidation with
formation of 41.
With the availability of this ketone, we turned to the
preparation of its coupling partner. The first step in this
direction involved the subjection of enantiopure keto
aldehyde 4219 to the Corey-Fuchs protocol.20 The treat-
ment of this bifunctional intermediate with methylene
dibromide and triphenylphosphine proceeded with an-
ticipated high chemoselectivity to give 43 (Scheme 8). The
ketone carbonyl was next reduced with sodium borohy-
dride in order to achieve its temporary masking. Exo
alcohol 45 predominated over the endo isomer 44 by a
factor of 5:1. Since these epimers were readily separated,
it was an easy matter to effect the oxidation of 44 for
recycling purposes. The next step involved the conver-
sion of 45 into the lithium acetylide by exposure to 3
equiv of n-butyllithium. With this accomplished, dry
cerium(III) chloride was added in advance of 41 in order
to curtail enolization and maximize the level of 1,2-
addition.21 The coupling proved to be highly stereo-
selective in favor of the S-carbinol 46 (14:1). The
The occasion to evaluate the C1-C4 option arose during
our probing of an alternate route to 1 in which the
C(CH3)2 bridge was projected to undergo the R-ketol
rearrangement along the “back” of the molecule as it is
typically drawn. This variant invited pursuit because of
the real possibility that some minimization of the total
number of steps could result. The issue of accessing
carbinol 52 involved the improvisations depicted in
Schemes 7 and 8. With D-glucose as starting material,
aldehyde 37 was obtained by preparation of the 4,6-O-
benzylidene derivative 36 in advance of periodate cleav-
age according to precedent.18 Following one-carbon chain
extension via Wittig olefination, the directed hydrobora-
tion of 38 with 9-BBN produced 39, which was subjected
(18) Baker, S. R.; Clissold, D. W.; McKillop, A. Tetrahedron Lett.
1988, 29, 991.
(19) Paquette, L. A.; Huber, S. K.; Thompson, R. C. J . Org. Chem.
1993, 58, 6874.
(20) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
(21) (a) Paquette, L. A., Ed. Encyclopedia of Reagents for Organic
Synthesis; Wiley: New York, 1995; Vol. 1, pp 1031-1034. (b) Dimitrov,
V.; Kostova, K.; Genov, M. Tetrahedron Lett. 1996, 37, 1787.

C Ring Construction via Intramolecular Aldolization
J . Org. Chem., Vol. 63, No. 23, 1998 8497
Sch em e 6
the trans olefin 47, the two hydroxyl groups in which
were differentiated by sequential Dess-Martin oxida-
tion24 and O-alkylation. Several of the more diagnostic
signal enhancements observed for 49 are shown in the
inset.
R-Oxygenation of this ketone was accomplished by the
action of oxone on the silyl enol ether.25 No complication
was experienced either during predominant formation of
the exo carbinol26 or during its protection as the MOM
ether.27 Addition of trans-1-propenyllithium28 to 51
provided the fully functionalized oxy-Cope rearrangement
precursor 52 in 86% yield.
The sequence of steps that would allow for examination
of the intramolecular aldol cyclization began with isomer-
ization of 52 in the presence of potassium hexamethyl-
disilazide and 18-crown-6 in THF at -78 °C. The desired
[3,3] sigmatropic rearrangement proceeded very effi-
ciently with formation of an enolate anion that was
directly oxygenated (O2, then Ph3P)29 in order to generate
53 (Scheme 9). In this instance, the configuration at C-8
is properly set as the direct consequence of the transition
state that is invariably adopted in the course of such
transpositions.8a When our initial pursuit of a sequence
involving desilylation30 of 53 and dual oxidation of the
two hydroxyl-bearing carbons was found to be unsuc-
cessful, the possibility of a stepwise approach to 56 was
eventually shown to be feasible. Thus, compound 53 was
first oxidized under Swern conditions31 to the R-diketone
level, as in 54 in advance of generation of aldehyde 56.
It was well-appreciated that successful C-ring closure in
this substrate depended on the absence of any disruption
from competing nucleophilic attack at either of the
neighboring carbonyl groups. This was accomplished by
treatment of 56 with tetrabutylammonium fluoride in
acetonitrile at 20 °C. This reagent is sufficiently basic
to deprotonate 56 and bring about the aldol process. The
stereochemistry of 57 was assessed following conversion
to acetate 58. The proximity of the R-acetoxy proton but
not the neighboring angular methyl group to the bridge-
head vinyl proton in 58 corroborated our expectation in
the form of C1-C4 (Figure 1) that the stereochemistry
resident in 56 is unsuited to achieving the proper
paclitaxel configuration at both C-7 and C-8.
Sch em e 7
expectation that equatorial attack would materialize on
the more stable chair conformer of 4122 was confirmed
by NOE analysis following conversion to the benzyl ether
49. Thus, Red-Al reduction23 of propargyl alcohol 46 gave
(24) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Ireland, R. E.; Liu, L. B. J . Org. Chem. 1993, 58, 2899.
(25) (a) Adam, W.; Chan, Y. Y.; Cremer, D.; Gauss, J .; Scheutzow,
D.; Schindler, M. J . Org. Chem. 1987, 52, 2800. (b) Adam, W.; Prechtl,
F. Chem. Ber. 1991, 124, 2369.
(26) Elmore, S. W.; Paquette, L. A. J . Org. Chem. 1995, 60, 889.
(27) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.
(28) Negri, J .; Morwick, T.; Doyon, J .; Wilson, P. D.; Hickey, E. R.;
Paquette, L. A. J . Am. Chem. Soc. 1993, 115, 12189.
(29) Paquette, L. A.; DeRussy, D. T.; Pegg, N. A.; Taylor, R. T.;
Zydowsky, T. M. J . Org. Chem. 1989, 54, 4576.
(30) Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.;
Roberts, S. M. Tetrahedron Lett. 1979, 3981.
(31) Mancuso, A. J .; Huang, S. L.; Swern, D. J . Org. Chem. 1978,
43, 2480.
(22) (a) Dancy, I.; Strydstrup, T.; Cre´visy, C.; Beau, J . M. J . Chem.
Soc., Chem. Commun. 1995, 799. (b) Carda, M.; Casabo´, P.; Gonza´lez,
F.; Rodr´ıguez, S.; Domingo, L. R.; Marco, J . A. Tetrahedron: Asymmetry
1997, 8, 559.
(23) (a) Mayer, H. J .; Rigassi, N.; Schwieter, U.; Weedon, B. C. L.
Helv. Chim. Acta 1976, 59, 1424. (b) Chan, K.-K.; Cohen, N.; De Noble,
J . P.; Specian, A. C., J r.; Saucy, G. J . Org. Chem. 1976, 41, 3497. (c)
J ones, T. K.; Denmark, S. E. Org. Synth. 1986, 64, 182. (d) Trost, B.;
Lautens, M. J . Am. Chem. Soc. 1987, 109, 1469. (e) Sola, L.; Castro,
J .; Moyano, A.; Pericas, M.; Riera, A. Tetrahedron Lett. 1992, 33, 2863.

8498 J . Org. Chem., Vol. 63, No. 23, 1998
Paquette et al.
Sch em e 8
Sch em e 9
In our original transition-state analysis, we had envi-
sioned that D1, the C* epimer of C1, would be conforma-
tionally constrained to produce D4. Reassurance that
this correlation holds came from those experiments
summarized in Scheme 10. The enantiopure diol 15 was
first heated with pyridinium p-toluenesulfonate in etha-
nol in order to effect hydrolysis and equilibration. Sub-
sequent treatment of the resulting 59 with DDQ in
anhydrous dichoromethane proceeded with exceptionally
high regio- and stereoselectivity. Thus, cyclization in-

C Ring Construction via Intramolecular Aldolization
J . Org. Chem., Vol. 63, No. 23, 1998 8499
Sch em e 10
volved exclusive nucleophilic attack by the primary
hydroxyl to form a 1,3-dioxane.32 Furthermore, only that
p-methoxybenzylidene acetal wherein the aromatic ring
is projected equatorially on a chairlike six-membered ring
was seen. The success of this tactic carried further with
conversion of primary carbinol 60 into iodide 61,11 protec-
tion of the tertiary carbinol as its trimethylsilylethoxy-
methyl ether,33 and fragmentation of the fully protected
furanose by way of the Bernet-Vasella protocol.34 Al-
dehyde 62 was alkenylated as before13 to deliver vinyl
iodide 63, thereby making possible halogen-metal ex-
change and 1,2-addition to 22. Carbinol 64 so formed
underwent charge-accelerated sigmatropic rearrange-
ment and direct methylation efficiently to produce 65.
As defined earlier in a related example,35 ketone 65 is
produced at -30 °C in the carbonyl-up geometry and with
the C-8 methyl substituent oriented â. Chemoselective
dihydroxylation of the bridgehead double bond in 65 was
accomplished without any attempt at optimization. Once
monoprotection of the diol had been accomplished as in
67, the side chain was elaborated to the aldehyde level
found in 68.
The amalgamation of the 1,3-dioxane ring in this
manner into the pendant C-3 unit destined to become
ring C appreciably restricts the conformational flexibility
attainable during the annulation process. The limiting
features of the aldol transition state are given by D2 in
Figure 1. This combination of factors is likely responsible
for the inability of 68 to undergo cyclization with an
acceptable degree of efficiency. The two tricyclic products
69 and 70 were produced in a 2:1 ratio (<30%) in addition
to p-methoxybenzaldehyde. The identities of the aldols
1
were suggested by comparative analyses of their H NMR
spectra with those of 28, 29, and 57. The most diagnostic
chemical shifts are those associated with the C-8 methyl
signals which in both 57 and 69 appear downfield at δ
1.46 and 1.43, respectively, because of their R-orientation.
In contrast, â-orientation of this substituent as in 29 (δ
1.32) is accompanied by characteristic shielding in excess
of 0.1 ppm. When the C ring carries a double bond as in
28 (δ 1.46) and 70 (δ 1.15), this trend is reversed.
Con clu sion s
Transition-state models that incorporate the stereo-
chemical consequences of C-4/C-5 substituents on the
intramolecular C-ring-forming aldol reactions in highly
functionalized bicyclo[6.2.1]undecanones related to pac-
litaxel are provided. When the C-4 and C-5 groups are
not covalently linked, the configurational pattern given
in transition-state model B2 is shown to be particularly
amenable to adoption of that chairlike arrangement
(32) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett.
1982, 23, 889. (b) Kloosterman, M.; Slaghek, T.; Hermans, J . P. G.;
van Boom, J . H. Recl. Trav. Chim. Pays-Bas 1984, 103, 335.
(33) Lipshutz, B. H.; Pegram, J . J . Tetrahedron Lett. 1980, 21, 3343.
(34) (a) Bernet, B.; Vasella, A. Helv. Chim. Acta 1979, 62, 1990. (b)
Coleman, R. S.; Dong, Y.; Carpenter, A. J . J . Org. Chem. 1992, 57,
3732.
(35) J ohnston, J . N.; Tsui, H.-C.; Paquette, L. A. J . Org. Chem. 1998,
63, 129.

8500 J . Org. Chem., Vol. 63, No. 23, 1998
Paquette et al.
10.7 Hz, 1 H), 4.44 (s, 2 H), 4.33 (s, 1 H), 4.11 (t, J ) 7.7 Hz,
1 H), 3.91-3.84 (m, 2 H), 3.80-3.67 (m, 9 H), 3.58-3.43 (m, 2
H), 1.44 (s, 3 H), 1.32 (s, 3 H), 1.30-1.16 (m, 6 H); 13C NMR
(75 MHz, CDCl3) ppm 159.1, 158.8, 139.9, 131.6, 130.3, 129.1
(2 C), 128.9 (2 C), 128.0 (2 C), 127.1 (2 C), 126.8, 113.6 (2 C),
113.5 (2 C), 106.9, 104.4, 82.1, 80.4, 77.2, 74.9, 73.1, 68.0, 66.4,
65.8, 65.3, 64.8, 55.2 (2 C), 26.4, 24.5, 15.51, 15.45; HRMS m/z
conducive to proper stereoinduction at C-7 and C-8 of the
paclitaxel C ring. The dominant stereochemical deter-
minants are believed to be the equatorial orientation of
at least two pendant groups and avoidance of 1,3-diaxial
interaction. An additional important stereochemical
influence appears upon incorporation of the oxygenated
centers at C-4 and C-5 into a 1,3-dioxane ring. When
this structural feature is present, the stereogenic carbon
labeled as C* exerts a dominant effect by preferentially
projecting the aryl group equatorially. From among the
four transition-state models D2-F 2, the first is subject
to destabilization as a consequence of a prominent 1,3-
diaxial interaction. The F 2 option is impossible because
of large interatomic distances. Of the remaining two, D2
is subject to a facial bias unsuited to paclitaxel construc-
tion. The stereoselective nature of three cyclizative
options is herein exemplified at the experimental level.
These results provide the first unambiguous picture of
the full intricacies of the intramolecular aldol cyclization.
Work directed to the preparation of a diastereoisomer of
the E1 class for the purpose of evaluating the level and
direction of operational stereoinduction will soon be
initiated and is expected to be the subject of a future
report.
(M+ - CH3) calcd for C35H45O9 609.3063, obsd 609.3095; [R]20
D
+5.0 (c 1.6, CHCl3).
Eth yl 2-O-Ben zyl-3-O-(p-m eth oxyben zyl)-2-C-[[(p-m eth -
oxyben zyl)oxy]m eth yl]-D-a r a bin ofu r a n osid e (18). A so-
lution of 17 (11.20 g, 17.95 mmol) in ethanol (420 mL)
containing pyridinium p-toluenesulfonate (770 mg, 3.07 mmol)
was refluxed for 1 h, concentrated, taken up in ether, washed
with water, dried, and reconcentrated. Purification of the
residue by chromatography on silica gel (elution with 40%
ethyl acetate in hexanes) furnished 18 as a colorless oil (9.30
g, 96%). This inseparable mixture of R- and â-anomers was
used without further characterization.
E t h yl
2-O-Ben zyl-5-d eoxy-5-iod o-3-O-(p -m et h oxy-
ben zyl)-2-C-[[(p-m eth oxyben zyl)oxy]m eth yl]-D-a r a bin o-
fu r a n osid e (19). A solution of 18 (9.29 g, 17.3 mmol) in 4:1
toluene/acetonitrile (185 mL) was treated with triphenylphos-
phine (13.56 g, 51.76 mmol) and imidazole (4.65 g, 68.4 mmol)
under nitrogen. The mixture was stirred at room temperature
for 10 min and at 50 °C for an identical period of time before
being returned to 20 °C, at which point iodine (8.73 g, 34.4
mmol) was introduced. The resulting suspension was stirred
at 70 °C for 1 h, cooled, diluted with ether, washed with water,
dried, and concentrated. Chromatography of the residue on
silica gel (elution with 15% ethyl acetate in hexanes) afforded
19 (9.66 g, 86%). A further column separation led to the
isolation of individual pure isomers.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. The
column chromatographic separations were performed with
Woelm silica gel (230-400 mesh). Solvents were reagent
grade and in most cases dried prior to use. The purity of all
compounds was shown to be >95% by TLC and high-field 1H
and 13C NMR. The high-resolution and fast-atom-bombard-
ment spectra were recorded at The Ohio State University
Campus Chemical Instrumentation Center. Elemental analy-
ses were performed at the Scandinavian Microanalytical
Laboratory, Herlev, Denmark, or at Atlantic Microlab, Inc.,
Norcross, GA.
Isom er A: IR (film, cm-1) 1612; 1H NMR (300 MHz, CDCl3)
δ 7.38-7.20 (m, 9 H), 6.87-6.82 (m, 4 H), 5.32 (s, 1 H), 4.90
(d, J ) 11.6 Hz, 1 H), 4.71-4.60 (m, 2 H), 4.53-4.45 (m, 4 H),
4.17 (d, J ) 6.2 Hz, 1 H), 4.05 (d, J ) 6.9, 6.4 Hz, 1 H), 3.86
(d, J ) 6.8 Hz, 2 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.59-3.49 (m,
1 H), 3.28 (d, J ) 6.9 Hz, 2 H), 1.26 (t, J ) 7.1 Hz, 3 H); 13C
NMR (75 MHz, CDCl3) ppm 159.3, 159.1, 139.5, 130.0, 129.9,
129.7 (2 C), 129.2 (2 C), 128.0 (2 C), 127.3 (2 C), 127.1, 113.7
(2 C), 113.6 (2 C), 102.0, 87.9, 86.6, 81.0, 73.4, 72.6, 71.2, 68.7,
63.8, 55.2, 15.3, 8.6 (one signal overlaps); HRMS m/z (M+
-
(rS,âR,4R)-r-Hydr oxy-â-[(p-m eth oxyben zyl)oxy]-r-[[(p-
m eth oxyben zyl)oxy]m eth yl]-2,2-d im eth yl-1,3-d ioxola n e-
4-p r op ion a ld eh yd e Dieth yl Aceta l (16). Sodium hydride
(380 mg, 15.8 mmol) was added to a solution of 157 (5.50 g,
13.3 mmol) in DMF (40 mL) at 0 °C. After 30 min of stirring
at this temperature, p-methoxybenzyl chloride was introduced,
and the mixture was stirred at room temperature for 1 h,
quenched with ice, diluted with saturated NH4Cl solution, and
extracted with ethyl acetate. The combined extracts were
washed with water, dried, and concentrated. The residue was
chromatographed on silica gel (elution with 30% ethyl acetate
in hexanes) to give 16 (6.29 g, 89%) as a colorless oil: IR (film,
cm-1) 3532, 1613; 1H NMR (300 MHz, CDCl3) δ 7.27-7.22 (m,
4 H), 6.87-6.83 (m, 4 H), 4.82 (d, J ) 10.7 Hz, 1 H), 4.62-
4.58 (m, 2 H), 4.51-4.40 (m, 3 H), 4.05-3.96 (m, 3 H), 3.79 (s,
6 H), 3.78-3.74 (m, 2 H), 3.61-3.55 (m, 2 H), 3.49-3.41 (m, 2
H), 2.89 (s, 1 H), 1.42 (s, 3 H), 1.33 (s, 3 H), 1.23-1.14 (m, 6
H); 13C NMR (75 MHz, CDCl3) ppm 158.8, 158.7, 130.7, 129.6,
129.0 (2 C), 128.9 (2 C), 113.3 (2 C), 113.2 (2 C), 107.1, 103.6,
78.8, 76.8, 76.2, 74.6, 72.8, 69.3, 65.4, 65.0, 64.7, 54.7 (2 C),
26.0, 24.7, 15.0 (2 C); HRMS m/z (M+) calcd for C29H42O9
OBn) calcd for C24H30IO6 541.1087, obsd 541.1113; [R]20D -25.2
(c 0.62, CHCl3).
Isom er B: IR (film, cm-1) 1612; 1H NMR (300 MHz, CDCl3)
δ 7.35-7.25 (m, 9 H), 6.91-6.85 (m, 4 H), 5.19 (s, 1 H), 4.63
(d, J ) 1.8 Hz, 2 H), 4.59-4.48 (m, 4 H), 4.26-4.21 (m, 1 H),
3.88 (d, J ) 1.5 Hz, 2 H), 3.82 (s, 3 H), 3.81 (s, 3 H), 3.78-3.76
(m, 2 H), 3.57-3.52 (m, 1 H), 3.22-3.11 (m, 2 H), 1.25 (t, J )
7.0 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 159.2, 159.1,
138.4, 130.3, 130.0, 129.5 (2 C), 129.3 (2 C), 128.2 (2 C), 127.4
(2 C), 127.3, 113.7 (2 C), 113.6 (2 C), 105.8, 88.7, 85.1, 84.3,
73.2, 72.5, 65.8, 65.7, 63.6, 55.2, 15.1, 7.1 (one signal overlaps);
HRMS molecular ion too fleeting for accurate measurement;
[R]20 +8.0 (c 0.9, CHCl3).
D
(2S,3R)-2-(Ben zyloxy)-3-[(p-m eth oxyben zyl)oxy]-2-[[(p-
m eth oxyben zyl)oxy]m eth yl]-4-p en ten a l (20). A solution
of 19 (9.66 g, 14.9 mmol) in methanol (105 mL) was treated
with zinc dust (9.60 g, 148 mmol), refluxed for 1.5 h, cooled to
room temperature, and filtered. The filtrate was diluted with
ether, washed with saturated NH4Cl solution and water, dried,
and concentrated. Chromatography of the residue on silica
gel (elution with 15% ethyl acetate in hexanes) gave 20 as a
colorless oil (6.62 g, 93%): IR (film, cm-1) 1737, 1612; 1H NMR
(300 MHz, CDCl3) δ 9.74 (s, 1 H), 7.39-7.28 (m, 5 H), 7.27-
7.15 (m, 4 H), 6.89-6.83 (m, 4 H), 5.98-5.89 (m, 1 H), 5.43-
5.29 (m, 2 H), 4.79 (s, 2 H), 4.60 (d, J ) 11.5 Hz, 1 H), 4.43-
4.33 (m, 3 H), 4.30 (d, J ) 11.5 Hz, 1 H), 3.81 (s, 3 H), 3.80 (s,
534.2828, obsd 534.2867; [R]20 +2.1 (c 3.3, CHCl3).
D
rS,âR,4R)-r-(Ben zyloxy)-â-[(p-m eth oxyben zyl)oxy]-r-
[[(p -m e t h o x y b e n z y l)o x y ]m e t h y l]-2,2-d i m e t h y l-1,3-
d ioxola n e-4-p r op ion a ld eh yd e Dieth yl Aceta l (17). So-
dium hydride (0.95 g, 39.6 mmol) was added to a solution of
16 (10.60 g, 19.8 mmol) in DMF (250 mL) at 0 °C. After 30
min of stirring at this temperature, benzyl bromide (6.78 g,
43.2 mmol) was introduced. The reaction mixture was proc-
essed in the predescribed manner to give 11.45 g (92%) of 17
as a colorless oil: IR (film, cm-1) 1612; 1H NMR (300 MHz,
CDCl3) δ 7.37-7.19 (m, 9 H), 6.90-6.84 (m, 4 H), 4.94-4.81
(m, 2 H), 4.79 (d, J ) 5.7 Hz, 2 H), 4.69 (s, 1 H), 4.55 (d, J )
3 H), 3.73 (d, J ) 10.2 Hz, 1 H), 3.66 (d, J ) 10.2 Hz, 1 H); 13
C
NMR (75 MHz, CDCl3) ppm 202.6, 159.3, 159.2, 138.9, 132.9,
129.8, 129.5, 129.4 (2 C), 129.3 (2 C), 128.1 (2 C), 127.3 (2 C),
120.4, 113.71 (2 C), 113.68 (2 C), 85.3, 80.8, 73.2, 70.5, 69.7,
68.2, 55.2 (two signals overlap); HRMS m/z (M+) calcd for
C29H32O6 476.2194, obsd 476.2212; [R]20D -18.9 (c 0.32, CHCl3).

C Ring Construction via Intramolecular Aldolization
J . Org. Chem., Vol. 63, No. 23, 1998 8501
(1Z,3S,4R)-2-(Ben zyloxy)-1-iod o-4-[(p-m eth oxyben zyl)-
oxy]-3-[[(p-m eth oxyben zyl)oxy]m eth yl]-1,5-h exadien e (21).
A solution of sodium hexamethyldisilazide (50 mL of 1 M in
THF, 50 mmol) was added to a suspension of (iodomethyl)-
triphenylphosphonium iodide (27.0 g, 50.9 mmol) in THF (170
mL) under nitrogen. This mixture was stirred at room
temperature for 5 min and at -78 °C for 10 min prior to the
introduction of 20 (14.0 g, 29.4 mmol) dissolved in THF (10
mL). After 1.5 h at -78 °C, water was added and the product
was extracted into ether. The combined organic extracts were
washed with water, dried, and concentrated in advance of
chromatographic purification (silica gel, elution with 15% ethyl
acetate in hexanes). There was isolated 17.25 g (98%) of 21
as a colorless oil: IR (film, cm-1) 1612; 1H NMR (300 MHz,
CDCl3) δ 7.44-7.41 (m, 2 H), 7.35-7.20 (m, 7 H), 6.91-6.86
(m, 4 H), 6.77 (d, J ) 8.9 Hz, 1 H), 6.68 (d, J ) 8.9 Hz, 1 H),
6.04-5.90 (m, 1 H), 5.40-5.31 (m, 2 H), 4.82 (d, J ) 11.6 Hz,
1 H), 4.67 (t, J ) 11.1 Hz, 2 H), 4.42 (s, 2 H), 4.38-4.33 (m, 2
H), 3.97 (d, J ) 9.8 Hz, 1 H), 3.82 (s, 3 H), 3.81 (s, 3 H), 3.71
(d, J ) 9.8 Hz, 1 H); 13C NMR (75 MHz, CDCl3) ppm 159.1,
139.4, 138.2, 134.1, 130.5, 130.1, 129.3 (2 C), 128.0 (2 C), 127.6,
126.9, 119.7, 113.7 (2 C), 113.6, 82.6, 81.5, 80.4, 72.9, 70.9,
70.4, 66.5, 55.3 (six signals overlap); HRMS m/z (M+ - PMB)
calcd for C22H24IO4 479.0681, obsd 479.0700; [R]20D -9.3 (c 0.28,
CHCl3).
(s, 3 H), 2.58-2.27 (m, 5 H), 2.14-2.01 (m, 3 H), 1.54-1.46
(m, 1 H), 1.19 (d, J ) 7.6 Hz, 3 H), 1.07 (s, 3 H), 0.98 (s, 3 H);
13C NMR (75 MHz, CDCl3) ppm 211.3, 159.0, 158.8, 146.5,
140.6, 136.8, 131.2, 130.8, 129.2 (2 C), 128.9 (2 C), 127.9 (2
C), 127.6 (2 C), 126.5, 124.6, 116.0, 113.62 (2 C), 113.57 (2 C),
95.0, 86.2, 84.4, 81.8, 72.7, 70.9, 70.4, 66.8, 55.5, 55.21, 55.16,
54.6, 47.9, 47.7, 45.4, 28.9, 26.9, 26.1, 23.2, 19.78, 19.76; HRMS
molecular ion too fleeting for accurate mass measurement;
[R]20 -31.4 (c 0.18, CHCl3).
D
(1S,2R,4R,5S,7S,8S)-5-[(1S,2R)-1-(Ben zyloxy)-4-h ydr oxy-
2-[(p -m et h oxyb en zyl)oxy]-1-[[(p -m et h oxyb en zyl)oxy]-
m e t h y l ]b u t y l ]-7 -(t e r t -b u t y l d i m e t h y l s i l o x y )-8 -h y -
dr oxy-2-(m eth oxym eth oxy)-4,11,11-tr im eth ylbicyclo[6.2.1]-
u n d eca n -3-on e (26). A solution of 24 (370 mg, 0.52 mmol)
in cold (0 °C) pyridine (7 mL) was admixed with osmium
tetraoxide (80 mg, 0.32 mmol), stirred at this temperature for
1.5 h, treated with a solution of sodium dithionite (2.0 g of
85% purity, 9.8 mmol) in water (7 mL), stirred at 20 °C for 12
h, and extracted with ether. The combined organic extracts
were washed with water, dried, and concentrated. The residue
was dissolved in DMF (0.7 mL), treated with imidazole (0.20
g, 2.9 mmol) and tert-butyldimethylsilyl chloride (0.27 g, 1.8
mmol), stirred for 2 h prior to quenching with saturated
Na2CO3 solution, and extracted with ether. The combined
organic layers were washed with water, dried, and concen-
trated. Chromatography of the residue on silica gel (elution
with 15% ethyl acetate in hexanes) gave 25 as a colorless oil
(208 mg, 76%). This material was used without further
purification.
(1S,2S,3R,4S)-2-[(1Z,3S,4R)-2-(Ben zyloxy)-4-[(p -m et h -
oxyb en zyl)oxy]-3-[[(p -m et h oxyb en zyl)oxy]m et h yl]-1,5-
h e x a d i e n y l]-3-(m e t h o x y m e t h o x y )-7,7-d i m e t h y l-1-
vin ylb icyclo[2.2.1]h ep t a n -2-ol (23). A cold (-78 °C),
magnetically stirred solution of 21 (2.35 g, 3.92 mmol) in
anhydrous ether (30 mL) under N2 was treated with n-
butyllithium (3 mL of 1.3 M, 3.9 mmol) and stirred for 2 min
prior to the introduction of 228d (0.87 g, 3.88 mmol) dissolved
in dry ether. After 40 min of continued agitation at -78 °C,
the reaction mixture was warmed to room temperature,
quenched with water, and extracted with ether. The combined
organic extracts were washed with water, dried, and concen-
trated to leave a residue that was purified chromatographically
(silica gel, elution with 15% ethyl acetate in hexanes). There
was isolated 2.46 g (91%) of 23 as a colorless oil: IR (film,
cm-1) 3340, 1612; 1H NMR (300 MHz, CDCl3) δ 7.37-7.28 (m,
5 H), 7.25-7.15 (m, 4 H), 6.85 (d, J ) 8.3 Hz, 4 H), 5.92-5.80
(m, 1 H), 5.67 (s, 1 H), 5.52 (s, 2 H), 5.42-5.29 (m, 3 H), 4.81-
4.68 (m, 4 H), 4.63-4.51 (m, 4 H), 4.48-4.36 (m, 3 H), 3.96 (d,
J ) 10.9 Hz, 1 H), 3.89 (d, J ) 10.9 Hz, 1 H), 3.795 (s, 3 H),
3.791 (s, 3 H), 3.56 (s, 1 H), 3.31 (s, 3 H), 1.84 (d, J ) 7.1 Hz,
1 H), 1.76-1.65 (m, 1 H), 1.58-1.48 (m, 1 H), 1.36-1.27 (m, 1
H), 1.21 (s, 3 H), 1.19-1.00 (m, 1 H), 0.64 (s, 3 H); 13C NMR
(75 MHz, CDCl3) ppm 159.13, 159.05, 140.2, 137.5, 136.0,
134.7, 130.4, 130.3, 129.3 (2 C), 128.9 (2 C), 128.0 (2 C), 127.7,
126.5, 118.5, 116.0, 113.7 (2 C), 113.6 (2 C), 96.1, 89.6, 84.0,
82.4, 78.0, 72.9, 71.7, 70.0, 67.0, 60.8, 55.21, 55.16, 50.8, 25.6,
24.4, 21.9, 21.7 (four signals overlap); HRMS molecular ion
A solution of borane in THF (2.7 mL of 1.0 M, 2.7 mmol)
was added at 0 °C under N2 to a solution of 2,3-dimethyl-2-
butene in the same solvent (2.7 mL of 1.0 M, 2.7 mmol). The
resulting solution was stirred at 0 °C for 50 min before a
solution of 25 (700 mg, 0.81 mmol) in THF (5 mL) was
introduced. The mixture was stirred at 0 °C for 100 min and
treated successively with aqueous NaOH solution (2.7 mL of
3 M, 8.1 mmol) and 30% hydrogen peroxide (2.1 mL, 32 mmol).
After further stirring for 30 min at room temperature, a
solution of sodium sulfite (3.0 g, 23.8 mmol) in water (10 mL)
was added, to be followed 30 min later by extraction with ether.
The combined extracts were washed with water, dried, and
concentrated to leave a residue that was chromatographed on
silica gel (elution with 50% ethyl acetate in hexanes) to give
26 as a white foam (512 mg, 72%): IR (film, cm-1) 3453, 1701,
1
1612; H NMR (300 MHz, CDCl3) δ 7.34-7.17 (m, 7 H), 7.11
(d, J ) 8.7 Hz, 2 H), 6.89 (d, J ) 8.7 Hz, 2 H), 6.84 (d, J ) 8.7
Hz, 2 H), 4.83 (d, J ) 11.8 Hz, 1 H), 4.75 (d, J ) 11.7 Hz, 1 H),
4.61 (d, J ) 10.7 Hz, 1 H), 4.57 (d, J ) 10.7 Hz, 1 H), 4.52-
4.47 (m, 3 H), 4.44 (dd, J ) 9.4, 2.4 Hz, 1 H), 4.33 (d, J ) 7.0
Hz, 1 H), 4.17 (s, 2 H), 3.95 (d, J ) 10.3 Hz, 1 H), 3.85-3.76
(m, 9 H), 3.75-3.65 (m, 1 H), 3.61 (dd, J ) 11.9, 2.2 Hz, 1 H),
3.25 (s, 3 H), 3.06-3.02 (m, 1 H), 2.64 (d, J ) 13.1 Hz, 1 H),
2.47-2.36 (m, 2 H), 2.23-2.10 (m, 2 H), 1.96-1.86 (m, 1 H),
1.79-1.64 (m, 4 H), 1.17 (d, J ) 6.4 Hz, 3 H), 1.06 (s, 3 H),
0.96 (s, 3 H), 0.89 (s, 9 H), 0.15 (s, 3 H), 0.11 (s, 3 H); 13C NMR
(75 MHz, CDCl3) ppm 212.3, 159.4, 159.1, 139.3, 129.7 (2 C),
129.3, 129.1 (2 C), 128.2 (2 C), 127.1, 126.7 (2 C), 113.8 (2 C),
113.6 (2 C), 94.9, 87.1, 82.8, 82.1, 74.3, 73.2, 70.1, 66.2, 60.6,
55.9, 55.7, 55.2, 50.4, 48.2, 35.6, 34.4, 32.1, 30.0, 25.8 (3 C),
18.1, 16.9, 10.6, -3.2, -4.8 (six signals overlap); FAB MS m/z
too fleeting for accurate mass measurement; [R]20 -34.1 (c
D
0.16, CHCl3).
(1S,2R,4R,5S,7E)-5-[(1S,2R)-2-(Ben zyloxy)-2-[(p-m eth -
oxyben zyl)oxy]-1-[[(p-m eth oxyben zyl)oxy]m eth yl]-3-bu -
ten yl]-2-(m eth oxym eth oxy)-4,11,11-tr im eth ylbicyclo[6.2.1]-
u n d ec-7-en -3-on e (24). A solution of potassium hexamethyl-
disilazide (11 mL of 0.5 M in toluene, 5.5 mmol) was added to
a solution of 23 (1.30 g, 1.86 mmol) and 18-crown-6 (1.45 g,
5.49 mmol) in dry THF (60 mL) cooled to -78 °C under N2.
The reaction mixture was stirred at -78 °C for 1 h and at -60
°C for 30 min before being returned to -78 °C in advance of
treatment with methyl iodide (1.18 g, 8.30 mmol) and another
40 min of stirring. After addition of water and warming to
room temperature, the product was extracted into ether,
washed with water, dried, concentrated, and chromatographed
on silica gel (elution with 15% ethyl acetate in hexanes). There
(M+) calcd for C50H74O11Si 878.50, obsd 878.60; [R]20 +7.1 (c
D
0.4, CHCl3).
(âR,γS,1S,4S,5R,7R,8S)-γ-(Ben zyloxy)-2-(ter t-b u t yld i-
m eth ylsiloxy)-1-h ydr oxy-â-[(p-m eth oxyben zyl)oxy]-γ-[[(p-
m eth oxyben zyl)oxy]m eth yl]-7-(m eth oxym eth oxy)-5,11,11-
t r im e t h yl-6-oxob icyclo[6.2.1]u n d e ca n e -4-b u t yr a ld e -
h yd e (27). A solution of oxalyl chloride (0.017 mL, 0.195
mmol) in CH2Cl2 (1 mL) was added to a solution of DMSO
(0.014 mL, 0.195 mmol) in CH2Cl2 (1 mL) at -78 °C under
N2. After 10 min, a solution of 26 (38 mg, 0.043 mmol) in the
same solvent (0.7 mL) was introduced, and stirring was
maintained at -78 °C for 40 min prior to the addition of
triethylamine (0.38 mL, 2.7 mmol), warming to 0 °C for 10
min, quenching with water, and extraction with ether. The
combined organic layers were washed with water, dried, and
was isolated 1.06 g (80%) of 24 as a white foam: IR (film, cm-1
)
1709, 1613; 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J ) 7.0 Hz,
2 H), 7.30-7.16 (m, 7 H), 6.90-6.80 (m, 4 H), 6.16-6.05 (m, 1
H), 5.31-5.10 (m, 3 H), 5.01-4.92 (m, 2 H), 4.67-4.63 (m, 2
H), 4.57-4.53 (m, 2 H), 4.50 (d, J ) 1.9 Hz, 1 H), 4.44-4.31
(m, 3 H), 4.06-4.00 (m, 2 H), 3.80 (s, 3 H), 3.77 (s, 3 H), 3.34

8502 J . Org. Chem., Vol. 63, No. 23, 1998
Paquette et al.
concentrated. Chromatography of the residue on silica gel
(elution with 30% ethyl acetate in hexanes) gave 27 as a
colorless oil (30 mg, 79%): IR (film, cm-1) 3454, 1723, 1612;
1H NMR (300 MHz, CDCl3) δ 9.73 (s, 1 H), 7.32-7.21 (m, 7
H), 7.08 (d, J ) 8.7 Hz, 2 H), 6.89 (d, J ) 8.7 Hz, 2 H), 6.82 (d,
J ) 8.7 Hz, 2 H), 4.95 (dd, J ) 7.5, 3.3 Hz, 1 H), 4.68 (s, 2 H),
4.51-4.45 (m, 5 H), 4.35 (d, J ) 7.0 Hz, 1 H), 4.16 (d, J ) 9.5
Hz, 2 H), 3.89 (d, J ) 9.7 Hz, 1 H), 3.81 (s, 3 H), 3.79 (s, 3 H),
3.61 (dd, J ) 11.4, 1.9 Hz, 1 H), 3.27 (s, 3 H), 3.10-3.04 (m, 1
H), 2.89-2.86 (m, 2 H), 2.61 (dd, J ) 13.6, 0.5 Hz, 1 H), 2.40-
2.30 (m, 3 H), 2.10-2.00 (m, 1 H), 1.76-1.60 (m, 4 H), 1.18 (d,
J ) 6.5 Hz, 3 H), 1.04 (s, 3 H), 0.95 (s, 3 H), 0.88 (s, 9 H), 0.13
(s, 3 H), 0.10 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 212.0,
200.3, 159.4, 159.2, 138.7, 130.1, 129.7 (2 C), 129.3 (2 C), 129.2,
128.2 (2 C), 127.3, 126.8 (2 C), 113.9 (2 C), 113.6 (2 C), 100.0,
95.0, 87.3, 82.4, 82.1, 73.9, 73.3, 70.7, 70.1, 66.2, 55.8, 55.2,
50.4, 48.1, 45.9, 35.4, 32.1, 31.9, 30.0, 28.6, 25.8 (3 C), 18.1,
16.9, 10.6, -3.3, -4.8 (two signals overlap); FAB MS m/z (M+)
2.46 (m, 2 H), 2.44-2.36 (m, 2 H), 2.27-2.14 (m, 1 H), 2.06-
2.01 (m, 1 H), 1.83-1.65 (m, 3 H), 1.32 (s, 3 H), 1.28 (d, J )
7.9 Hz, 1 H), 1.05 (s, 3 H), 0.99 (s, 3 H), 0.86 (s, 9 H), 0.13 (s,
3 H), 0.11 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 213.0, 159.1,
139.8, 130.3, 129.9, 129.4 (2 C), 128.9 (2 C), 128.1 (2 C), 127.0,
126.9 (2 C), 113.8 (2 C), 113.7 (2 C), 96.2, 84.4, 83.5, 82.0, 81.1,
73.3, 72.6, 70.7, 69.7, 67.3, 66.9, 59.7, 56.8, 56.0, 55.2, 49.9,
40.9, 33.8, 32.7, 31.6, 29.6, 28.1, 25.8 (3 C), 18.0, 17.2, 10.6,
-3.2, -4.6 (two signals overlap); FAB MS m/z (M+) calcd for
C
50H72O11Si 876.48, obsd 876.53; [R]20 -42.0 (c 0.04, CHCl3).
D
(1S,2R,4S,4a S,6R,7S,10S,11S,12a S)-1-(Ben zyloxy)-11-
(t er t -b u t y ld i m e t h y ls i lo x y )d o d e c a h y d r o -4,10-d i h y -
droxy-2-[(p-methoxybenzyl)oxy]-1-[[(p-methoxybenzyl)oxy]-
methyl]-6-(methoxymethoxy)-4a,13,13-trimethyl-7,10-meth-
a n oben zocyclod ecen -5(1H)-on e 4-Ben zoa te (30). A solu-
tion of 29 (8 mg, 0.009 mmol), benzoic anhydride (100 mg, 0.44
mmol), and DMAP (50 mg, 0.41 mmol) in CH2Cl2 (1.5 mL) was
stirred at 20 °C for 6 h, quenched with saturated NaHCO3
solution (1 mL), and extracted with ether (3 × 10 mL). The
combined extracts were washed with water, dried, and con-
centrated. The residue was purified by chromatography (silica
gel, elution with 20% ethyl acetate in hexanes) to provide 30
as a colorless oil (7 mg, 79%): IR (film, cm-1) 3458, 1723, 1612;
1H NMR (300 MHz, CDCl3) δ 7.92 (d, J ) 7.4 Hz, 2 H), 7.55 (t,
J ) 7.4 Hz, 1 H), 7.41-7.21 (m, 9 H), 7.17 (d, J ) 8.5 Hz, 2H),
6.84-6.81 (m, 4H), 5.31 (dd, J ) 11.5, 3.3 Hz, 1 H), 4.89 (d, J
) 11.3 Hz, 1 H), 4.73 (d, J ) 11.3 Hz, 1 H), 4.64 (d, J ) 11.4
Hz, 1 H), 4.60 (s, 1 H), 4.59 (d, J ) 11.7 Hz, 1 H), 4.44 (d, J )
11.9 Hz, 1 H), 4.38 (d, J ) 10.9 Hz, 1 H), 4.19 (d, J ) 2.5 Hz,
1 H), 4.17 (s, 1 H), 4.06 (d, J ) 10.1 Hz, 1 H), 4.04 (d, J ) 6.7
Hz, 1 H), 3.93-3.82 (m, 2 H), 3.80 (s, 3 H), 3.79 (s, 3 H), 3.73-
3.70 (m, 1 H), 3.07 (s, 3 H), 2.71-2.40 (m, 5 H), 2.07-1.67 (m,
4 H), 1.61 (s, 3 H), 1.32-1.20 (br m, 1 H), 1.03 (s, 3 H), 0.97 (s,
3 H), 0.87 (s, 9 H), 0.15 (s, 6 H); 13C NMR (75 MHz, CDCl3)
ppm 212.4, 165.4, 159.2, 159.1, 139.5, 133.1, 130.1, 130.0,
129.8, 129.5 (2 C), 129.4 (2 C), 129.0 (2 C), 128.4 (2 C), 128.2
(2 C), 127.1, 127.0 (2 C), 113.8 (2 C), 113.7 (2 C), 94.4, 82.3,
82.0, 81.0, 77.2, 75.3, 73.4, 70.6, 69.7, 67.2, 67.0, 57.3, 56.3,
55.5, 55.2, 50.0, 41.0, 33.4, 31.6, 29.4, 29.0, 27.3, 25.8 (3 C),
18.1, 17.3, 12.5, -3.2, -4.6 (one signal overlaps); FAB MS m/z
(M+) calcd for C57H76O12Si 980.51, obsd 980.58; [R]20D +17.7 (c
0.03, CHCl3).
calcd for C50H72O11Si 876.48, obsd 876.53; [R]20 +7.9 (c 0.15,
D
CHCl3).
(1S,4S,4aS,6S,7S,10S,11S,12aS)-1-(Benzyloxy)-11-(tert-butyl-
d im eth ylsiloxy)-4,4a ,6,7,8,9,10,11,12,12a -d eca h yd r o-4,10-
d ih yd r oxy-1-[[(p -m et h oxyb en zyl)oxy]m et h yl]-6-(m et h -
oxym et h oxy)-4a ,13,13-t r im et h yl-7,10-m et h a n ob en zocy-
clod ecen -5(1H)-on e (28). A. Use of Sod iu m Hyd r oxid e.
A mixture of 27 (34 mg, 0.039 mmol) and aqueous NaOH
solution (0.28 mL of 0.5 M, 0.14 mmol) in methanol (1 mL)
and THF (0.2 mL) was stirred at -5 °C for 30 h, quenched
with saturated NH4Cl solution (1 mL), warmed to room
temperature, and extracted with ether (3 × 15 mL). The
combined extracts were washed with water, dried, and con-
centrated. Product 28, purified by chromatography on silica
gel (elution with 30% ethyl acetate in hexanes), was isolated
as a colorless oil (17 mg, 65% based on recovered 27 (3 mg)):
1
IR (film, cm-1) 3457, 1697; H NMR (300 MHz, C6D6) δ 7.44
(d, J ) 7.2 Hz, 2 H), 7.23-7.15 (m, 5 H), 6.80 (d, J ) 8.6 Hz,
2 H), 6.08 (dd, J ) 10.6, 2.6 Hz, 1 H), 5.97 (d, J ) 10.7 Hz, 1
H), 4.75 (br s, 1 H), 4.56 (d, J ) 11.5 Hz, 1 H), 4.44-4.18 (m,
7 H), 3.73 (d, J ) 10.2 Hz, 1 H), 3.64 (d, J ) 10.2 Hz, 1 H),
3.54 (d, J ) 4.7 Hz, 1 H), 3.27 (s, 3 H), 3.26-3.23 (m, 1 H),
2.98 (s, 3 H), 2.83 (dd, J ) 11.3, 0.4 Hz, 1 H), 2.55-2.08 (m, 5
H), 1.82-1.72 (m, 1 H), 1.46 (s, 3 H), 1.41 (s, 3 H), 1.29 (s, 3
H), 1.10 (t, J ) 7.0 Hz, 1 H), 0.82 (s, 9 H), 0.16 (s, 3 H), 0.14
(s, 3 H); 13C NMR (75 MHz, C6D6) ppm 213.4, 159.8, 139.7,
136.0, 130.7, 129.5 (2 C), 128.6 (2 C), 127.6, 114.1 (2 C), 100.2,
96.3, 84.4, 82.0, 80.1, 74.2, 73.7, 73.6, 69.8, 65.8, 61.0, 56.9,
55.8, 54.8, 50.4, 37.9, 33.2, 32.4, 29.9, 26.9, 25.9 (3 C), 18.2,
18.1, 12.0, -3.2, -4.4 (two signals overlap); FAB MS m/z (M+)
(1S,2R,4R,5S,7E)-5-[(1S,2R)-2-(Ben zyloxy)-2-[(p-m eth -
oxyben zyl)oxy]-1-[[(p-m eth oxyben zyl)oxy]m eth yl]-3-bu -
ten yl]-2-(m eth oxym eth oxy)-4,11,11-tr im eth ylbicyclo[6.2.1]-
u n d ec-7-en -3-on e (31). A solution of potassium hexameth-
yldisilazide (0.44 mL of 0.5 M, 0.22 mmol) in toluene was added
to a solution of 23 (53 mg, 0.076 mmol) and 18-crown-6 (59
mg, 0.23 mmol) in THF (3 mL) at 0 °C under N2. The reaction
mixture was stirred at 0 °C for 5 min, cooled to -78 °C, treated
with methyl iodide (45 mg, 0.32 mmol) dissolved in THF (1
mL), stirred at -78 °C for 2 h, quenched with water, warmed
to 20 °C, and extracted with ether. The combined extracts
were processed in the usual way, and the residue was
chromatographed on silica gel (elution with 10% ethyl acetate
in hexanes) to give 49 mg (91%) of 31 as a white foam: IR
calcd for C42H62O9Si 738.42, obsd 738.47; [R]20 +65.1 (c 0.08,
D
C6H6).
B. Use of Tita n iu m Tetr a isop r op oxid e. A solution of
titanium isopropoxide in CH2Cl2 (0.1 mL of 0.5 M, 0.05 mmol)
was added to a solution of 27 (15 mg, 0.017 mmol) in THF (1
mL). This mixture was stirred at 20 °C for 8 h, quenched with
saturated NH4Cl solution, and extracted with ether. Adapta-
tion of the preceding workup led to the isolation of 10 mg (79%)
of 28.
1
(film, cm-1) 1687, 1613; H NMR (300 MHz, CDCl3) δ 7.32-
(1S,2R,4S,4a S,6R,7S,10S,11S,12a S)-1-(Ben zyloxy)-11-
(tert-butyldimethylsiloxy)dodecahydro-4,10-dihydroxy-2-[(p-
m e t h o x y b e n z y l )o x y ]-1 -[[(p -m e t h o x y b e n z y l )o x y ]-
methyl]-6-(methoxymethoxy)-4a,13,13-trimethyl-7,10-methano-
ben zocyclod ecen -5(1H)-on e (29). A solution of lithium
hydroxide in water (0.6 mL of 0.5 M, 0.3 mmol) was added to
a solution of 27 (95 mg, 0.108 mmol) in THF (5 mL) at -12
°C. The reaction mixture was stirred at this temperature for
17 h and worked up in the predescribed manner. Chroma-
tography on silica gel (elution with 15% ethyl acetate in
hexanes) gave 29 (18.2 mg) and returned unreacted 27 (58.2
7.21 (m, 9 H), 6.89-6.85 (m, 4 H), 6.09-5.97 (m, 1 H), 5.47-
5.27 (m, 3 H), 5.01 (d, J ) 11.7 Hz, 1 H), 4.69 (d, J ) 6.7 Hz,
1 H), 4.59-4.51 (m, 3H), 4.49 (d, J ) 11.2 Hz, 1 H), 4.35 (d, J
) 9.9 Hz, 2 H), 4.12 (d, J ) 11.1 Hz, 1 H), 3.87 (d, J ) 5.1 Hz,
2 H), 3.82 (s, 3 H), 3.79 (s, 3 H), 3.70 (d, J ) 9.7 Hz, 1 H),
3.51-3.38 (m, 2 H), 3.37 (s, 3 H), 2.43-2.01 (m, 4 H), 1.93-
1.88 (m, 3 H), 1.37 (s, 3 H), 1.03 (d, J ) 3.6 Hz, 3 H), 1.02 (s,
3 H); 13C NMR (75 MHz, CDCl3) ppm 212.4, 159.0, 158.8, 146.5,
139.6, 135.8, 130.9, 130.4, 129.1 (2 C), 128.6 (2 C), 128.1 (2
C), 127.4 (2 C), 127.0, 124.1, 120.1, 113.6 (2 C), 113.5 (2 C),
96.1, 87.4, 85.0, 81.9, 73.0, 72.5, 69.4, 65.6, 56.1, 55.2, 53.4,
45.7, 41.8, 40.6, 26.1, 23.6, 23.0, 22.0, 18.0 (two signals
overlap); FAB MS m/z (M+) calcd for C44H56O8 712.40, obsd
mg) for an adjusted yield of 49%: colorless oil; IR (film, cm-1
)
3444, 1699, 1612; 1H NMR (300 MHz, CDCl3) δ 7.32-7.20 (m,
7 H), 7.16 (d, J ) 8.6 Hz, 2 H), 6.87-6.79 (m, 4 H), 4.87 (d, J
) 11.3 Hz, 1 H), 4.74 (d, J ) 11.5 Hz, 1 H), 4.62-4.50 (m, 4
H), 4.43 (s, 2 H), 4.35 (d, J ) 11.0 Hz, 1 H), 4.23 (s, 1 H), 4.16-
4.12 (m, 1 H), 3.96 (s, 2 H), 3.80 (s, 3 H), 3.79 (s, 3 H), 3.78-
3.69 (m, 2 H), 3.34 (s, 3 H), 3.25 (d, J ) 5.0 Hz, 1 H), 2.58-
712.47; [R]20 -33.1 (c 0.38, CHCl3).
D
[2-[[[(1S ,2R ,3R ,4R ,5S ,7E )-5-[(1S ,2R )-1-(Be n zyloxy)-
2-[(p -m et h oxyb en zyl)oxy]-1-[[(p -m et h oxyb en zyl)oxy]-
m eth yl]-3-bu ten yl]-2-(m eth oxym eth oxy)-4,11,11-tr im eth -
ylb icyclo[6.2.1]u n d ec-7-en -3-yl]oxy]m et h oxy]et h yl]t r i-

C Ring Construction via Intramolecular Aldolization
J . Org. Chem., Vol. 63, No. 23, 1998 8503
m eth ylsila n e (32). Lithium aluminum hydride (200 mg, 5.26
mmol) was added to a solution of 31 (860 mg, 1.21 mmol) in
dry ether (30 mL), and the resulting suspension was stirred
at 20 °C for 3 h, quenched with water, and extracted with
ether. Following the predescribed workup and chromatogra-
phy on silica gel (elution with 15% ethyl acetate in hexanes),
there was isolated 303 mg (35%) of the R-carbinol and 260 mg
(30%) of the â-carbinol.
osmium tetraoxide (85 mg, 0.33 mmol) in pyridine (0.5 mL)
was added to a solution of 31 (246 mg, 0.35 mmol) in pyridine
(7 mL) at 0 °C. The reaction mixture was stirred at this
temperature for 2 h, treated with
a solution of sodium
dithionite (1.4 g of 85% purity, 6.8 mmol) in water (10 mL),
stirred at 20 °C overnight, and extracted with ether. The
combined extracts were washed with water, dried, and con-
centrated. Chromatography of the residue on silica gel (elution
with 30% ethyl acetate in hexanes) afforded 33 as a colorless
r-Isom er : colorless oil; IR (film, cm-1) 3446, 1612; 1H NMR
(300 MHz, CDCl3) δ 7.36-7.20 (m, 9 H), 6.89 (d, J ) 8.6 Hz,
4 H), 6.04-5.92 (m, 1 H), 5.39 (dd, J ) 10.2, 2.0 Hz, 1 H),
5.30-5.24 (m, 2 H), 4.96 (d, J ) 11.8 Hz, 1 H), 4.68 (d, J ) 6.2
Hz, 1 H), 4.61-4.59 (m, 2 H), 4.54-4.46 (m, 3 H), 4.41 (d, J )
8.6 Hz, 1 H), 4.37 (d, J ) 11.3 Hz, 1 H), 4.16 (d, J ) 11.2 Hz,
1 H), 3.81 (s, 3 H), 3.81-3.80 (m, 1 H), 3.79 (s, 3 H), 3.67 (d,
J ) 9.9 Hz, 1 H), 3.58 (d, J ) 4.2 Hz, 1 H), 3.47 (d, J ) 10.9
Hz, 1 H), 3.38 (s, 3 H), 3.07-2.84 (m, 1 H), 2.83-2.78 (m, 1
H), 2.68-2.45 (m, 3 H), 2.17-1.99 (m, 3 H), 1.73 (br s, 1 H),
1.32 (s, 3 H), 1.23 (d, J ) 6.3 Hz, 3 H), 1.07 (s, 3 H); 13C NMR
(75 MHz, CDCl3) ppm 159.0, 158.7, 145.0, 139.6, 136.0, 131.1,
130.4, 129.2 (2 C), 128.6, 128.5, 128.1 (2 C), 127.2 (2 C), 126.9,
120.7, 120.2, 113.9, 113.7, 113.5, 96.3, 91.7, 85.4, 82.6, 73.2,
73.1, 72.4, 69.3, 65.3, 55.8, 55.2, 50.4, 45.9, 37.4, 34.5, 26.9,
24.3, 23.8, 22.5, 13.2 (three signals overlap); FAB MS m/z (M+)
1
oil (190 mg, 74%): IR (film, cm-1) 3440, 1613; H NMR (300
MHz, CDCl3) δ 7.33-7.21 (m, 9 H), 6.88-6.84 (m, 4 H), 6.03-
5.91 (m, 1 H), 5.40-5.25 (m, 2 H), 4.92 (d, J ) 12.2 Hz, 1 H),
4.67-4.56 (m, 3H), 4.54 (d, J ) 10.1 Hz, 1 H), 4.39-4.26 (m,
3 H), 4.13-4.06 (m, 2 H), 3.81 (s, 3 H), 3.79 (s, 3 H), 3.61 (d,
J ) 10.1 Hz, 1 H), 3.56-3.42 (m, 1 H), 3.39 (s, 3 H), 3.21 (dd,
J ) 12.1, 6.6 Hz, 1 H), 2.84 (m, 1 H), 2.50 (s, 1 H), 2.08-1.66
(m, 9 H), 1.41 (s, 3 H), 1.17 (d, J ) 6.6 Hz, 3 H), 1.05 (s, 3 H);
13C NMR (75 MHz, CDCl3) ppm 159.1, 158.9, 139.6, 135.3,
130.8, 130.2, 129.2 (2 C), 128.9 (2 C), 128.1 (2 C), 126.9 (2 C),
126.8, 120.3, 113.7 (2 C), 113.6 (2 C), 103.4, 97.7, 92.8, 84.9,
83.2, 81.7, 79.4, 73.1, 71.7, 69.7, 65.2, 55.6, 55.2, 50.4, 46.8,
38.2, 37.9, 32.7, 30.0, 25.0, 24.7, 22.8, 15.1 (one signal
overlaps); FAB MS m/z (M+) calcd for C44H56O10 746.40, obsd
746.49; [R]20 +7.8 (c 0.50, CHCl3).
D
calcd for C44H58O8 714.41, obsd 714.48; [R]20 -48.7 (c 0.40,
(2R,4S,5R)-2-P h en yl-4-vin yl-m -d ioxa n -5-ol (38). To a
mixture of 4,6-O-benzylidene-D-glucose18 (36, 14.0 g, 0.052
mmol) and NaHCO3 (4.37 g, 0.052 mmol) in CH2Cl2 (200 mL)
and water (100 mL) was added sodium periodate (25.0 g, 0.12
mol) in small portions. After 30 min of agitation, the solvents
were removed in vacuo, and the white residue was extracted
five times with ethyl acetate. The combined extracts were
dried, filtered, and evaporated to give aldehyde 37, which was
used directly without purification.
D
CHCl3).
â-Isom er : colorless oil; IR (film, cm-1) 3541, 1613; 1H NMR
(300 MHz, CDCl3) δ 7.38-7.17 (m, 9 H), 6.88-6.81 (m, 4 H),
6.14-5.92 (m, 1 H), 5.44-5.39 (m, 1 H), 5.32-5.24 (m, 2 H),
4.80-4.50 (m, 7 H), 4.45-4.38 (m, 2 H), 4.29 (s, 1 H), 4.27 (d,
J ) 3.4 Hz, 1 H), 4.09 (d, J ) 8.8 Hz, 1 H), 3.79 (s, 6 H), 3.39
(s, 3 H), 3.30 (dd, J ) 9.4, 1.1 Hz, 1 H), 3.13 (s, 1 H), 2.63-
2.41 (m, 4 H), 2.20-1.96 (m, 4 H), 1.51-1.47 (m, 1 H), 1.02 (d,
J ) 8.3 Hz, 3 H), 0.97 (s, 3 H), 0.80 (s, 3 H); 13C NMR (75
MHz, CDCl3) ppm 158.8, 145.5, 139.8, 135.9, 131.0, 130.9,
129.1 (2 C), 128.9 (2 C), 128.1 (2 C), 128.06 (2 C), 127.0, 119.3
(2 C), 118.7 (2 C), 113.6, 113.5, 98.0, 90.6, 86.8, 84.3, 73.0, 72.9,
69.8, 69.4, 66.7, 56.0, 55.2, 51.6, 45.6, 44.9, 38.5, 26.7, 24.4,
24.2, 23.1, 20.8, 15.8 (two signals overlap); FAB MS m/z (M+)
A solution of methyltriphenylphosphonium iodide (21.4 g,
0.053 mol) in dry THF (100 mL) at 0 °C was treated with
potassium hexamethyldisilazide (106 mL of 0.5 M in toluene,
0.053 mmol), stirred at 0 °C for 1 h, and treated with the above
aldehyde dissolved in THF (100 mL). The resultant brown
suspension was allowed to warm to 20 °C, stirred for an
additional 3 h, and quenched with saturated NH4Cl solution.
Ether was added, and the white solids were removed by
filtration through a Celite pad. The filtrate was extracted with
ether, the combined organics were dried and concentrated, and
the residue was chromatographed on silica gel. Elution with
25% ethyl acetate in hexanes yielded 7.44 g (69% overall) of
calcd for C44H58O8 714.41, obsd 714.43; [R]20 -8.3 (c 0.21,
D
CHCl3).
SEM chloride (470 mg, 2.82 mmol) was added to a solution
of the R-alcohol (270 mg, 0.378 mmol) and diisopropylethyl-
amine (0.5 mL, 2.9 mmol) in DMF (1 mL). The reaction
mixture was stirred at room temperature for 2.5 h, treated
with saturated NaHCO3 solution (5 mL), and extracted with
ether. The combined organic extracts were washed with water,
dried, concentrated, and chromatographed on silica gel. Elu-
tion with 15% ethyl acetate in hexanes provided 295 mg (92%)
of 32 as a colorless oil: IR (film, cm-1) 1613; 1H NMR (300
MHz, C6D6) δ 7.44 (d, J ) 7.2 Hz, 2 H), 7.35 (d, J ) 8.6 Hz, 2
H), 7.28 (d, J ) 8.6 Hz, 2 H), 7.19 (d, J ) 7.1 Hz, 2 H), 7.09 (d,
J ) 7.3 Hz, 1 H), 6.84 (d, J ) 8.0 Hz, 2 H), 6.82 (d, J ) 8.4 Hz,
2 H), 6.18-6.06 (m, 1 H), 5.57-5.52 (m, 1 H), 5.26-5.14 (m, 3
H), 4.74-4.61 (m, 6 H), 4.55 (d, J ) 10.7 Hz, 1 H), 4.44 (d, J
) 11.3 Hz, 1 H), 4.25 (d, J ) 11.3 Hz, 1 H), 4.16 (d, J ) 10.7
Hz, 1 H), 3.88 (d, J ) 4.9 Hz, 1 H), 3.82 (d, J ) 9.8 Hz, 1 H),
3.79-3.70 (m, 2 H), 3.68-3.52 (m, 2 H), 3.32 (s, 3 H), 3.30 (s,
3 H), 3.29 (s, 3 H), 3.28-3.24 (m, 1 H), 3.13-2.99 (m, 2 H),
2.81-2.68 (m, 2 H), 2.21-2.06 (m, 2 H), 1.93-1.89 (m, 1 H),
1.67 (d, J ) 6.5 Hz, 3 H), 1.54 (s, 3 H), 1.52-1.44 (m, 1 H),
1.08 (s, 3 H), 0.96-0.86 (m, 2 H), -0.04 (s, 9 H); 13C NMR (75
MHz, C6D6) ppm 159.6, 159.5, 144.8, 140.2, 136.9, 131.5, 130.7,
129.7 (2 C), 129.6 (2 C), 128.5 (2 C), 127.2, 121.6, 120.3, 113.9
(2 C), 96.8, 93.5, 87.7, 86.3, 83.1, 76.8, 73.5, 70.1, 65.9, 65.6,
55.6, 54.7, 51.8, 46.6, 38.4, 35.3, 27.2, 24.8, 24.6, 23.1, 22.7,
18.5, 15.0, -1.3 (four signals overlap); FAB MS m/z (M+) calcd
1
38 as a white solid: mp 87-89 °C; IR (film, cm-1) 3443; H
NMR (300 MHz, CDCl3) δ 7.55-7.35 (m, 5 H), 5.98 (ddd, J )
17.3, 10.5, 6.6 Hz, 1 H), 5.54 (s, 1 H), 5.50 (dt, J ) 17.3, 1.3
Hz, 1 H), 5.37 (dd, J ) 10.6, 1.0 Hz, 1 H), 4.33-4.25 (m, 1 H),
4.03-3.98 (t, J ) 7.3 Hz, 1H), 3.65-3.54 (m, 2 H), 2.19 (br s,
1 H); 13C NMR (75 MHz, CDCl3) ppm 137.4, 134.5, 129.0, 128.2
(2 C), 126.1 (2 C), 119.0, 100.8, 83.1, 70.7, 65.1; HRMS m/z
(M+) calcd 206.0943, obsd 206.0936; [R]20 -59.1 (c 1.96,
D
CHCl3).
Anal. Calcd for C12H14O3: C, 69.89; H, 6.84. Found: C,
69.99; H, 6.85.
(2R,4S,5R)-5-H yd r oxy-2-p h en yl-m -d ioxa n e-4-et h a n ol
(39). A solution of 38 (7.44 g, 0.036 mol) in THF (50 mL) at
0 °C was treated with a solution of 9-BBN (217 mL of 0.5 M
in THF, 0.108 mol), allowed to warm to 20 °C, and stirred
overnight. The mixture was cooled in an ice-water bath,
treated carefully with aqueous sodium hydroxide (60 mL, 2
N) followed by hydrogen peroxide (60 mL, 30% in water),
allowed to warm to 20 °C, and stirred for another 2 h. Solvents
were removed in vacuo to leave a white residue, which was
partitioned between ether and water. The separated aqueous
phase was extracted with ether (2×), and the combined organic
phases were dried, filtered, and concentrated. Chromato-
graphic purification of the residue on silica gel (elution with
25% ethyl acetate in hexanes) provided 7.0 g (87%) of 39 as a
colorless oil: IR (film, cm-1) 3395; 1H NMR (300 MHz, CDCl3)
δ 7.49-7.32 (m, 5 H), 5.46 (s, 1 H), 4.30-4.20 (m, 1 H), 3.94
(br s, 2 H), 3.85-3.70 (m, 2 H), 3.69-3.62 (m, 1 H), 3.60-3.52
(m, 2 H), 2.12-2.01 (m, 1 H), 1.96-1.87 (m, 1 H); 13C NMR
(75 MHz, CDCl3) ppm 137.5, 129.0, 128.2 (2 C), 126.0 (2 C),
for C50H72O9Si 844.49, obsd 844.62; [R]20 -32.8 (c 0.12,
D
benzene).
Analogous treatment of the â-alcohol gave the corresponding
derivative in 91% yield.
(1S,2S,5S,6R,7R,8R,9S)-9-[(1S,2R)-1-(Ben zyloxy)-2-[(p-
m eth oxyben zyl)oxy]-1-[[(p-m eth oxyben zyl)oxy]m eth yl]-
3-b u t e n yl]-6-(m e t h oxym e t h oxy)-8,12,12-t r im e t h yl-11-
oxa tr icyclo[5.3.1.12,5]d od eca n e-2,7-d iol (33). A solution of

8504 J . Org. Chem., Vol. 63, No. 23, 1998
Paquette et al.
1
100.9, 81.0, 71.0, 65.6, 59.3, 35.6; HRMS m/z (M+) calcd for
C12H16O4 224.1048, obsd 224.1049; [R]20D -23.0 (c 3.79, CHCl3).
45: colorless oil, IR (film, cm-1) 3453; H NMR (300 MHz,
CDCl3) δ 6.57 (s, 1 H), 4.38 (ddd, J ) 7.5, 3.6, 3.6 Hz, 1 H),
2.12 (d, J ) 3.2 Hz, 1 H), 1.89-1.60 (m, 7 H), 1.09 (s, 3 H),
0.86 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 138.4, 88.3, 76.1,
57.8, 48.3, 43.9, 39.7, 29.1, 27.3, 20.5, 20.1; HRMS m/z (M+)
(2R,4S,5R)-4-[2-(ter t-Bu tyldim eth ylsiloxy)eth yl]-2-ph en -
yl-m -d ioxa n -5-ol (40). A solution of 39 (9.56 g, 0.043 mol)
in CH2Cl2 (100 mL) at 0 °C was treated with imidazole (4.36
g, 0.064 mol) and tert-butyldimethylsilyl chloride (7.07 g, 0.049
mol), warmed to 20 °C, and stirred overnight. The mixture
was quenched with saturated NaHCO3 solution, and the
separated phase was extracted with CH2Cl2 (2×). The com-
bined organic solutions were dried, filtered, and concentrated.
Chromatography of the residue on silica gel (elution with 25%
ether in hexanes) afforded 40 as a colorless oil (12.5 g, 87%):
IR (film, cm-1) 3405; 1H NMR (300 MHz, CDCl3) δ 7.51-7.33
(m, 5 H), 5.47 (s, 1 H), 4.56 (s, 1 H), 4.38-4.34 (m, 1 H), 3.94-
3.77 (m, 2 H), 3.65-3.56 (m, 3 H), 2.04-1.99 (m, 2 H), 0.94 (s,
9 H), 0.134 (s, 3 H), 0.127 (s, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 137.9, 128.8, 128.2 (2 C), 126.1 (2 C), 100.9, 81.8, 71.0,
66.1, 60.3, 37.7, 25.8 (3 C), 18.2, -5.5, -5.6; HRMS m/z (M+)
calcd for C11H16Br2O 321.9568, obsd 321.9567; [R]20 -64.7 (c
D
7.02, CHCl3).
Anal. Calcd for C11H16Br2O: C, 40.77; H, 4.98. Found: C,
40.81; H, 4.94.
(2R ,4S ,5S )-4-[2-(t er t -Bu t yld im e t h ylsiloxy)e t h yl]-5-
[[(1R,2R,4R)-2-h yd r oxy-7,7-d im eth ylbicyclo[2.2.1]h ep t-1-
yl]eth yn yl]-2-p h en yl-m -d ioxa n -5-ol (46). Into a solution of
45 (4.31 g, 13.4 mmol) in THF (30 mL) at -78 °C was
introduced a solution of n-butyllithium (25.1 mL of 1.6 M in
hexanes, 40.2 mmol). The mixture was stirred at -78 °C for
1 h and cannulated into a stirred suspension of 41 (3.0 g, 8.93
mmol) and anhydrous cerium trichloride [prepared from
cerium trichloride heptahydrate (16.6 g, 44.6 mol)] in THF (100
mL) at -78 °C. The mixture was allowed to warm to 20 °C
overnight. After being returned to -78 °C, the mixture was
quenched with saturated NH4Cl solution, and the white
suspension was warmed to room temperature and diluted with
ether and water. The solid was removed by filtration through
a pad of Celite. The aqueous phase was extracted with ether
(2×) and the combined organic solutions were dried, filtered,
and concentrated. Chromatography of the residue on silica
gel (elution with 25% ethyl acetate in hexanes) gave diol 46
(2.90 g, 65%) as the major product: white solid, mp 92-94
calcd for C18H30O4Si 338.1913, obsd 338.1908; [R]20 -26.6 (c
D
3.57, CHCl3).
(2R,4S)-4-[2-(ter t-Bu tyld im eth ylsiloxy)eth yl]-2-p h en yl-
m -d ioxa n -5-on e (41). To a solution of 40 (3.85 g, 0.011 mol)
in CH2Cl2 (50 mL) was added the Dess-Martin periodinane
(7.25 g, 0.017 mol). The mixture was stirred for 30 min,
diluted with ether, filtered, and washed with aqueous NaOH
(1.0 N) and brine prior to drying and filtration. The removal
of solvents in vacuo followed by chromatography on silica gel
(elution with 25% ether in hexanes) gave 41 (3.44 g, 90%) as
a colorless oil: IR (film, cm-1) 1737; 1H NMR (300 MHz, CDCl3)
δ 7.57-7.36 (m, 5 H), 5.95 (s, 1 H), 4.66 (dd, J ) 7.8, 4.0 Hz,
1 H), 4.51 and 4.43 (ABq, J ) 17.3 Hz, 2 H), 3.91-3.78 (m, 2
H), 2.33-2.22 (m, 1 H), 2.07-1.96 (m, 1 H), 0.93 (s, 9 H), 0.09
(s, 6 H); 13C NMR (75 MHz, CDCl3) ppm 205.7, 137.2, 129.1,
128.3 (2 C), 126.0 (2 C), 99.1, 79.4, 72.0, 58.0, 32.9, 25.8 (3 C),
18.3, -5.4, -5.5; HRMS m/z (M+) calcd for C18H28O4Si 336.1757,
°C; IR (film, cm-1) 3401, 1737; H NMR (300 MHz, CDCl3) δ
1
7.50-7.31 (m, 5 H), 5.57 (s, 1 H), 4.19 (d, J ) 11.5 Hz, 1 H),
4.11 (dd, J ) 9.5, 2.2 Hz, 1 H), 4.02 (d, J ) 11.5 Hz, 1 H),
3.81-3.74 (m, 3 H), 3.72 (s, 1 H), 3.03 (br s, 1 H), 2.25-2.14
(m, 1 H), 2.01-1.70 (m, 7 H), 1.33-1.25 (m, 1 H), 1.18 (s, 3
H), 0.96 (s, 3 H), 0.91 (s, 9 H), 0.06 (s, 6 H); 13C NMR (75 MHz,
CDCl3) ppm 137.6, 129.0, 128.2 (2 C), 125.9 (2 C), 101.5, 87.6,
81.9, 79.9, 78.0, 76.1, 66.0, 58.3, 50.5, 49.7, 44.0, 39.5, 32.7,
32.6, 27.2, 25.9 (3 C), 21.1, 20.4, 18.3, -5.3, -5.5; HRMS m/z
obsd 336.1738; [R]20 -33.7 (c 4.60, CHCl3).
D
(1S,4R)-1-(2,2-Dibr om ovin yl)-7,7-dim eth ylbicyclo[2.2.1]-
h ep ta n -2-on e (43). To a solution of triphenylphosphine (12.6
g, 0.084 mol) in CH2Cl2 (50 mL) at 0 °C was added solid carbon
tetrabromide (8.0 g, 0.024 mol) in small portions. The result-
ant brown suspension was stirred at 0 °C for 5 min, at which
point a solution of 4219 (2.0 g, 0.012 mol) in CH2Cl2 (5 mL)
was treated dropwise. After 10 min at this temperature, ether
was added and the solid was removed by filtration through a
pad of Celite. Removal of solvents from the filtrate followed
by chromatography on silica gel (elution with 10% ether in
hexanes) gave 43 as a white solid (3.0 g, 78%): mp 72-73 °C;
(M+
-
tBu - H2O) calcd for C25H33O4Si 425.2148, obsd
425.2150; [R]20 -22.8 (c 1.76, CHCl3).
D
Anal. Calcd for C29H44O5Si: C, 69.56; H, 8.86. Found: C,
69.65; H, 8.92.
(2R,4S,5S)-4-[2-(ter t-Bu tyld im eth ylsiloxy)eth yl]-5-[(E)-
2-[(1S,2R,4R)-2-h yd r oxy-7,7-d im eth ylbicyclo[2.2.1]h ep t-
1-yl]vin yl]-2-p h en yl-m -d ioxa n -5-ol (47). A solution of 46
(838 mg, 1.68 mmol)) in THF (15 mL) at 0 °C was treated with
a solution of Red-Al (2.46 mL of 3.4 M in toluene, 8.38 mmol).
The cooling bath was removed, and the mixture was stirred
at 20 °C for another 2 h. After being returned to an ice-water
bath, the mixture was quenched carefully with saturated
NH4Cl solution. The mixture was diluted with ether and
water, solids were removed by filtration, and layers were
separated. The aqueous phase was extracted with ether (5×),
the combined organic solutions were dried and filtered, and
the concentrate was chromatographed on silica gel (elution
with 25% ethyl acetate in hexanes). There was obtained 639
mg (76%) of 47 as a colorless oil: IR (film, cm-1) 3417, 1664;
1H NMR (300 MHz, CDCl3) δ 7.53-7.30 (m, 5 H), 6.20 (d, J )
16.3 Hz, 1 H), 5.58 (s, 1 H), 5.30 (d, J ) 16.3 Hz, 1 H), 4.03
(dd, J ) 9.3, 2.3 Hz, 1 H), 3.93 (s, 2 H), 3.80-3.64 (m, 4 H),
2.93 (br s, 1 H), 1.90-1.71 (m, 7 H), 1.19 (s, 3 H), 1.14-1.01
(m, 2 H), 0.91 (s, 9 H), 0.80 (s, 3 H), 0.054 (s, 3 H), 0.046 (s, 3
H); 13C NMR (75 MHz, CDCl3) ppm 137.9, 131.8, 128.8, 128.2,
128.1 (2 C), 125.9 (2 C), 101.3, 80.3, 79.1, 76.6, 70.7, 58.7, 54.9,
47.9, 45.5, 40.2, 31.6, 29.5, 27.0, 25.9 (3 C), 20.8, 20.3, 18.3,
-5.3, -5.4; HRMS m/z (M+ - C7H7O2) calcd for C22H39O3Si
1
IR (film, cm-1) 1743; H NMR (300 MHz, CDCl3) δ 6.39 (s, 1
H), 2.39 (dt, J ) 18.3, 3.3 Hz, 1 H), 2.24-2.14 (m, 2 H), 2.07-
1.95 (m, 2 H), 1.90 (d, J ) 18.3 Hz, 1 H), 1.47-1.39 (m, 1 H),
0.99 (s, 3 H), 0.92 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm
211.3, 132.9, 91.4, 65.2, 49.1, 43.1, 42.2, 27.2, 25.9, 20.2, 19.9;
HRMS m/z (M+) calcd for C11H14Br2O 319.9412, obsd 319.9405;
[R]20 -93.4 (c 4.68, CHCl3).
D
Anal. Calcd for C11H14Br2O: C, 41.03; H, 4.38. Found: C,
40.92; H, 4.32.
Bor oh yd r id e Red u ction of 43. A solution of 43 (556 mg,
1.74 mmol) in methanol (10 mL) at 0 °C was treated with
sodium borohydride (66 mg, 1.74 mmol) in small portions. The
cooling bath was removed, and the mixture was allowed to
warm to room temperature, stirred for a further 2 h, and freed
of solvent. Chromatographic separation of the epimeric alco-
hols (silica gel, elution with 10% ethyl acetate in hexanes)
provided in turn the less polar exo alcohol 45 (443 mg, 79%),
followed by the more polar endo alcohol 44 (88 mg, 16%).
379.2668, obsd 379.2668; [R]20 -51.5 (c 4.34, CHCl3).
D
44: white solid, mp 128-129 °C; 1H NMR (300 MHz, CDCl3)
δ 6.53 (s, 1 H), 4.50 (br d, J ) 9.5 Hz, 1 H), 2.62-2.55 (m, 1
H), 2.35-2.25 (m, 1 H), 1.87-1.62 (m 4 H), 1.42-1.35 (m, 1
H), 1.06 (dd, J ) 13.3, 3.4 Hz, 1 H), 0.96 (s, 3 H), 0.91 (s, 3 H);
13C NMR (75 MHz, CDCl3) 139.1, 86.9, 75.2, 58.7, 51.6, 44.3,
(1S,4R)-1-[(E)-2-[(2R,4S,5S)-4-[2-(ter t-Bu t yld im et h yl-
siloxy)ethyl]-5-hydroxy-2-phenyl-m-dioxan-5-yl]vinyl]-7,7-di-
m eth ylbicyclo[2.2.1]h ep ta n -2-on e (48). A solution of 47
(607 mg, 1.21 mmol) in CH2Cl2 (15 mL) was treated with the
Dess-Martin periodinane (771 mg, 1.81 mmol), stirred for 1
h, diluted with ether, and filtered. The filtrate was washed
with 1 N NaOH and brine, dried, filtered, and concentrated.
Chromatography of the residue on silica gel (elution with 20%
ethyl acetate in hexanes) delivered 48 (491 mg, 81%) as a
38.4, 28.5, 23.4, 20.8, 19.1; HRMS m/z (M+) calcd for C11H16
-
Br2O 321.9568, obsd 321.9565; [R]20 +5.9 (c 2.49, CHCl3).
D
Anal. Calcd for C11H16Br2O: C, 40.77; H, 4.98. Found: C,
40.67; H, 4.96.

C Ring Construction via Intramolecular Aldolization
J . Org. Chem., Vol. 63, No. 23, 1998 8505
1
colorless oil: IR (film, cm-1) 3460, 1743; H NMR (300 MHz,
4.78 (d, J ) 11.3 Hz, 1 H), 4.57 (d, J ) 12.8 Hz, 1 H), 4.10-
4.01 (m, 2 H), 3.88-3.74 (m, 3 H), 3.42 (br s, 1 H), 2.16-1.89
(m, 5 H), 1.59-1.39 (m, 2 H), 1.11 (s, 3 H), 0.95 (s, 9 H), 0.94
(s, 3 H), 0.10 (s, 3 H), 0.08 (s, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 217.5, 139.5, 138.5, 131.2, 128.9, 128.3 (2 C), 128.2 (2 C),
127.6, 127.4 (2 C), 127.1, 126.4 (2 C), 101.7, 79.7, 77.6, 74.6,
70.8, 65.8, 62.4, 59.0, 49.6, 49.0, 31.3, 26.1 (3 C), 25.8, 25.1,
21.56, 20.6, 18.4, -5.2, -5.3; FAB MS m/z (M+ + H) calcd
CDCl3) δ 7.54-7.35 (m, 5 H), 5.94 (d, J ) 16.2 Hz, 1 H), 5.57
(s, 1 H), 5.52 (dd, J ) 16.2, 1.0 Hz, 1 H), 4.04 (t, J ) 5.5 Hz,
1 H), 3.93 and 3.90 (ABq, J ) 11.6 Hz, 2 H), 3.82-3.71 (m, 2
H), 3.12 (d, J ) 0.9 Hz, 1 H), 2.44 (ddd, J ) 18.3, 4.8, 2.2 Hz,
1 H), 2.14 (t, J ) 3.9 Hz, 1 H), 2.05-1.79 (m, 5 H), 1.58-1.39
(m, 2 H), 0.96 (s, 3 H), 0.94 (s, 3 H), 0.90 (s, 9 H), 0.049 (s, 3
H), 0.046 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 216.2, 137.9,
131.0, 128.9, 128.2 (2 C), 126.8, 125.9 (2 C), 101.3, 79.4, 76.2,
70.4, 62.9, 58.7, 48.8, 43.6, 43.2, 31.9, 27.1 (2 C), 25.9 (3 C),
607.35, obsd 607.43; [R]20 +0.22 (c 2.67, CHCl3).
D
(1S,3R,4S)-1-[(E)-2-[(2R,4S,5S)-5-(Ben zyloxy)-4-[2-(ter t-
bu tyldim eth ylsiloxy)eth yl]-2-ph en yl-m-dioxan -5-yl]vin yl]-
3-(m et h oxym et h oxy)-7,7-d im et h ylbicyclo[2.2.1]h ep t a n -
2-on e (51). A solution of 50 (190 mg, 0.31 mmol) in CH2Cl2
(5 mL) at 0 °C was treated with diisopropylethylamine (0.32
mL, 1.84 mmol) and MOM chloride (0.084 mL, 1.11 mmol).
The cooling bath was removed, and the mixture was stirred
overnight, quenched with saturated NaHCO3 solution, and
diluted with ether. The separated aqueous phase was ex-
tracted with ether. The combined organic solutions were dried,
filtered, and freed of solvent to leave a residue that was
chromatographed on silica gel. Elution with 18% ethyl acetate
in hexanes delivered 51 as a colorless oil (160 mg, 79%): IR
(film, cm-1) 1755; 1H NMR (300 MHz, CDCl3) δ 7.60-7.26 (m,
10 H), 5.90 (d, J ) 16.5 Hz, 1 H), 5.66 (s, 1 H), 5.51 (d, J )
16.5 Hz, 1 H), 4.92 (d, J ) 11.3 Hz, 1 H), 4.87 (d, J ) 6.6 Hz,
1 H), 4.76 (d, J ) 11.3 Hz, 1 H), 4.75 (d, J ) 6.6 Hz, 1 H), 4.55
(d, J ) 12.9 Hz, 1 H), 4.06-4.02 (m, 1 H), 4.00 (d, J ) 13.0
Hz, 1 H), 3.74 (s, 1 H), 3.82-3.45 (m, 2 H), 3.44 (s, 3 H), 2.20
(d, J ) 4.4 Hz, 1 H), 2.10-1.92 (m, 4 H), 1.56-1.46 (m, 2 H),
1.10 (s, 3 H), 0.94 (s, 3 H), 0.93 (s, 9 H), 0.07 (s, 3 H), 0.06 (s,
3 H); 13C NMR (75 MHz, CDCl3) ppm 214.6, 139.4, 138.4, 131.1,
128.7, 128.1 (2 C), 128.0 (2 C), 127.5, 127.2 (2 C), 126.9, 126.2
(2 C), 101.5, 96.6, 81.2, 79.5, 74.5, 70.7, 65.6, 62.2, 58.9, 55.5,
48.7, 48.4, 31.2, 25.9 (4 C), 24.9, 21.3, 20.3, 18.2, -5.3, -5.5;
FAB MS m/z (M+ + H) calcd for C38H55O7Si 651.19, obsd
20.2, 19.5, 18.2, -5.3, -5.4; HRMS m/z (M+ - Bu) calcd for
t
C25H35O5Si 443.2254, obsd 443.2279; [R]20 +16.0 (c 3.94,
D
CHCl3).
Anal. Calcd for C29H44O5Si: C, 69.56; H, 8.86. Found: C,
69.37; H, 8.79.
(1S,4R)-1-[(E)-2-[(2R,4S,5S)-5-(Ben zyloxy)-4-[2-(ter t-bu -
tyld im eth ylsiloxy)eth yl]-2-p h en yl-m -d ioxa n -5-yl]vin yl]-
7,7-d im eth ylbicyclo[2.2.1]h ep ta n -2-on e (49). To a suspen-
sion of potassium hydride (606 mg, 15.1 mmol) in dry THF
(10 mL) at 0 °C was added a solution of 48 (3.78 g, 7.56 mol)
in THF (10 mL). The mixture was stirred at 0 °C for 15 min,
benzyl bromide (1.80 mL, 15.1 mol) and a catalytic amount of
tetra-n-butylammonium iodide were added, and warming to
20 °C was effected. After 30 min, the mixture was recooled in
an ice-water bath, quenched carefully with ethyl acetate
followed by saturated NH4Cl solution, and diluted with water
and ether. The separated aqueous layer was extracted with
ether, and the combined organic solutions were dried, filtered,
and concentrated. Chromatography of the residue on silica
gel (elution with 18% ethyl acetate in hexanes) furnished 49
(3.9 g, 83%) as a colorless oil: IR (film, cm-1) 1742; H NMR
1
(300 MHz, CDCl3) δ 7.62-7.25 (m, 10 H), 5.84 (d, J ) 16.4
Hz, 1 H), 5.64 (s, 1 H), 5.49 (d, J ) 16.4 Hz, 1 H), 4.91 (d, J )
11.4 Hz, 1 H), 4.75 (d, J ) 11.4 Hz, 1 H), 4.55 (d, J ) 12.9 Hz,
1 H), 4.04 (dd, J ) 11.4, 2.1 Hz, 1 H), 4.00 (d, J ) 12.9 Hz, 1
H), 3.85-3.70 (m, 2H), 2.46 (ddd, J ) 18.3, 4.7, 2.2 Hz, 1 H),
2.16 (t, J ) 4.1 Hz, 1 H), 2.10-1.86 (m, 6 H), 1.61-1.42 (m, 1
651.33; [R]20 +16.2 (c 5.98, CHCl3).
D
(1S,2S,3R,4S)-1-[(E)-2-[(2R,4S,5S)-5-(Ben zyloxy)-4-[2-
(ter t-bu tyld im eth ylsiloxy)eth yl]-2-p h en yl-m-d ioxa n -5-yl]-
v i n y l]-3-(m e t h o x y m e t h o x y )-7,7-d i m e t h y l-2-[(E )-1-
p r op en yl]bicyclo[2.2.1]h ep ta n -2-ol (52). To a solution of
trans-1-bromo-1-propene (0.20 mL, 2.36 mmol) in THF (5 mL)
at -78 °C under N2 was added tert-butyllithium (2.70 mL, 4.72
mmol), and the mixture was stirred at -78 °C for 15 min. A
solution of 51 (428 mg, 0.66 mmol) in THF (5 mL) was
introduced, and the reaction mixture was stirred at -78 °C
for another 30 min, quenched with saturated NaHCO3 solu-
tion, and diluted with ether. The separated aqueous layer was
extracted with ether, and the combined organic solutions were
dried, filtered, and concentrated. Purification of the residue
on silica gel (elution with 18% ethyl acetate in hexanes)
H), 0.95 (s, 3 H), 0.92 (s, 12 H), 0.06 (s, 3 H), 0.05 (s, 3 H); 13
C
NMR (75 MHz, CDCl3) ppm 216.2, 139.5, 138.4, 130.8, 128.7,
128.1 (2 C), 128.0 (3 C), 127.2 (2 C), 126.9, 126.3 (2 C), 101.5,
79.6, 74.5, 70.7, 65.6, 63.1, 58.9, 48.8, 43.6, 43.2, 31.2, 27.0,
26.9, 25.9 (3 C), 20.2, 19.5, 18.2, -5.3, -5.5; HRMS m/z (M+)
calcd for C36H50O5Si 590.3428, obsd 590.3466; [R]20 -13.8 (c
D
4.38, CHCl3).
(1S,3R,4S)-1-[(E)-2-[(2R,4S,5S)-5-(Ben zyloxy)-4-[2-(ter t-
bu tyldim eth ylsiloxy)eth yl]-2-ph en yl-m-dioxan -5-yl]vin yl]-
3-h yd r oxy-7,7-d im eth ylbicyclo[2.2.1]h ep ta n -2-on e (50). A
solution of diisopropylamine (0.16 mL, 1.14 mmol) in THF (5
mL) at -78 °C was treated with a solution of n-butyllithium
(0.71 mL of 1.6 M hexanes, 1.14 mmol) and later with a
solution of 49 (380 mg, 0.64 mmol) in THF (4 mL). The
mixture was stirred at -78 °C for another 1 h, and trimeth-
ylsilyl chloride (0.15 mL, 1.14 mmol) was introduced, followed
by warming to 20 °C and further treatment with triethylamine
(1 mL). The white suspension was diluted with ether and
washed with saturated NaHCO3 solution. The separated
organic layer was dried, filtered, and concentrated. The silyl
enol ether was dissolved in a mixture of water (10 mL), acetone
(10 mL), and CH2Cl2 (10 mL). A catalytic amount of 18-
crown-6 and solid NaHCO3 (5.0 g, 59.5 mmol) were added, and
the mixture was cooled to 0 °C. Oxone (4.67 g, 7.60 mmol)
was introduced, the cooling bath was removed, and the mixture
was stirred for another 1 h prior to dilution with water and
CH2Cl2. The organic layer was extracted twice with ether, and
the combined organic solutions were dried, filtered, and
concentrated. The residue was dissolved in THF (10 mL),
cooled to 0 °C, treated with TBAF (0.76 mL of 1.0 M in THF,
0.76 mmol), stirred at 0 °C for 1 h, and finally diluted with
ether and water. The aqueous layer was extracted with ether,
and the combined organic solutions were dried, filtered, and
concentrated. Chromatography of the residue on silica gel
(elution with 25% ethyl acetate in hexanes) gave 50 as a
afforded 52 (393 mg, 86%) as a colorless oil: IR (film, cm-1
)
3533; 1H NMR (300 MHz, CDCl3) δ 7.57-7.22 (m, 10 H), 6.12
(d, J ) 16.8 Hz, 1 H), 5.71 (dq, J ) 15.3, 6.4 Hz, 1 H), 5.63 (s,
1 H), 5.54 (dd, J ) 15.4, 1.2 Hz, 1 H), 5.20 (d, J ) 16.7 Hz, 1
H), 4.79 (d, J ) 11.3 Hz, 1 H), 4.71 (s, 2 H), 4.65 (d, J ) 11.2
Hz, 1 H), 4.48 (d, J ) 12.8 Hz, 1 H), 4.00 (d, J ) 12.8 Hz, 1 H),
3.98 (dd, J ) 9.9, 2.2 Hz, 1 H), 3.82-3.71 (m, 2 H), 3.69 (s, 1
H), 3.39 (s, 3 H), 2.94 (s, 1 H), 2.09-1.91 (m, 2 H), 1.95 (d, J
) 5.1 Hz, 1 H), 1.89-1.74 (m, 1 H), 1.71 (dd, J ) 6.3, 1.0 Hz,
3 H), 1.60-1.49 (m, 1 H), 1.49-1.35 (m, 1 H), 1.32 (s, 3 H),
1.12-1.03 (m, 1 H), 0.89 (s, 9 H), 0.79 (s, 3 H), 0.03 (s, 3 H),
0.02 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 139.7, 138.6,
135.6, 131.4, 129.4, 128.7, 128.1 (2 C), 128.0 (2 C), 127.5 (2
C), 127.0, 126.3 (2 C), 124.4, 101.5, 97.1, 88.2, 82.3, 80.3, 74.6,
70.6, 65.4, 59.1, 58.8, 55.6, 50.6, 50.5, 31.1, 26.3, 26.0 (3 C),
24.2, 22.6, 22.2, 18.3, 18.0, -5.3, -5.4; FAB MS m/z (M+ + H)
calcd for C41H61O7Si 693.42, obsd 693.44; [R]20 -11.7 (c 1.54,
D
CHCl3).
(1S,2R,5R,6S,7E)-6-[(2R,4S,5S)-5-(Ben zyloxy)-4-[2-(ter t-
b u t yld im et h ylsiloxy)et h yl]-2-p h en yl-m -d ioxa n -5-yl]-4-
h yd r oxy-2-(m eth oxym eth oxy)-5,11,11-tr im eth ylbicyclo-
[6.2.1]u n d ec-7-en -3-on e (53). To a solution of 52 (48 mg,
0.069 mmol) and 18-crown-6 (38 mg, 0.14 mmol) in THF (5
mL) at -78 °C under oxygen was added a solution of tri-
phenylphosphine (18 mg, 0.069 mmol) in THF (0.2 mL). The
1
colorless oil: IR (film, cm-1) 3442, 1750; H NMR (300 MHz,
CDCl3) δ 7.62-7.26 (m, 10 H), 5.93 (d, J ) 16.5 Hz, 1 H), 5.69
(s, 1 H), 5.53 (d, J ) 16.5 Hz, 1 H), 4.94 (d, J ) 11.3 Hz, 1 H),

8506 J . Org. Chem., Vol. 63, No. 23, 1998
Paquette et al.
solution was transferred to a beaker of cold silica gel, suction
filtered, and washed with ether. The filtrate was concentrated
and chromatographed (silica gel, elution with 33% ethyl
acetate in hexanes). After the recovery of unreacted 52 (8 mg,
17%), there was obtained 35 mg (72%; 81% based on recovered
52) of 53 as a colorless oil: IR (film, cm-1) 3406, 1706; 1H NMR
(300 MHz, CDCl3) δ 7.53-7.20 (m, 10 H), 5.59 (s, 1 H), 5.14
(d, J ) 11.7 Hz, 1 H), 5.07 (d, J ) 7.1 Hz, 1 H), 5.06 (d, J )
11.7 Hz, 1 H), 4.64 (d, J ) 6.7 Hz, 1 H), 4.48 (d, J ) 13.1 Hz,
1 H), 4.43 (d, J ) 6.7 Hz, 1 H), 4.36 (dd, J ) 10.2, 1.6 Hz, 1
H), 4.26 (d, J ) 13.1 Hz, 1 H), 4.18 (d, J ) 2.0 Hz, 1 H), 3.88
(dt, J ) 10.0, 4.1 Hz, 1 H), 3.79-3.73 (m, 1 H), 3.43 (t, J )
10.3 Hz, 1 H), 3.37 (s, 3 H), 2.62 (q, J ) 10.2 Hz, 1 H), 2.57-
2.26 (m, 4 H), 2.22 (dd, J ) 8.2, 1.8 Hz, 1 H), 2.15-2.11 (m, 1
H), 2.06-1.96 (m, 1 H), 1.77-1.68 (m, 1 H), 1.52 (d, J ) 11.3
Hz, 1 H), 1.38 (d, J ) 6.3 Hz, 3 H), 1.21 (s, 3 H), 1.09 (s, 3 H),
0.90 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 208.5, 145.3, 140.0, 138.4, 128.8, 128.2 (2 C),
128.0, 127.1 (2 C), 126.9, 126.2, 125.7 (2 C), 101.0, 95.3, 86.2,
79.2, 76.8, 74.3, 70.9, 67.9, 58.8, 55.7, 53.2, 47.5, 45.6, 39.1,
32.1, 26.0 (3 C), 25.9, 25.6, 23.7, 20.3, 19.4, 18.4, -5.3, -5.4;
FAB MS m/z (M+ + H) calcd for C41H61O8Si 709.41, obsd
26.3, 24.6, 23.5, 20.7, 15.8; FAB MS m/z (M+ + H) calcd for
C
35H45O8 593.31, obsd 593.41; [R]20 -50.7 (c 0.91, CHCl3).
D
(2R,4S,5S)-5-(Ben zyloxy)-4-[(1E,3S,4R,7R,8S)-7-(m eth -
oxym et h oxy)-4,11,11-t r im et h yl-5,6-d ioxob icyclo-[6.2.1]-
u n dec-1-en -3-yl]-2-ph en yl-m-dioxan e-4-acetaldeh yde (56).
A solution of 55 (92 mg, 0.16 mmol) in CH2Cl2 (5 mL) was
treated with the Dess-Martin periodinane (99 mg, 0.23 mmol),
stirred for 30 min, and diluted with ether. The solid was
filtered, and the filtrate was concentrated. Chromatography
on silica gel (elution with 18% ethyl acetate in hexanes)
furnished 56 as a yellow oil (81 mg, 89%): IR (film, cm-1) 1727,
1
1698; H NMR (300 MHz, CDCl3) δ 9.76 (s, 1 H), 7.49-7.27
(10 H), 5.64 (s, 1 H), 5.45 (d, J ) 10.3 Hz, 1 H), 5.14 (d, J )
11.3 Hz, 1 H), 5.04 (d, J ) 11.3 Hz, 1 H), 4.71-4.61 (m, 4 H),
4.58 (d, J ) 13.1 Hz, 1 H), 4.46 (d, J ) 6.8 Hz, 1 H), 4.15 (d,
J ) 13.0 Hz, 1 H), 3.91-3.81 (m, 1 H), 3.36 (s, 3 H), 2.99-
2.95 (m, 2 H), 2.66 (t, J ) 10.4 Hz, 1 H), 2.27-2.08 (m, 2 H),
2.02-1.90 (m, 1 H), 1.74-1.60 (m, 1 H), 1.27 (d, J ) 6.5 Hz, 3
H), 1.19 (s, 3 H), 1.05 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm
203.3, 201.1, 199.6, 147.5, 138.9, 137.6, 129.2, 128.4 (2 C),
128.3 (2 C), 127.3, 127.2 (2 C), 126.2 (2 C), 122.9, 101.1, 95.8,
82.8, 78.0, 73.9, 71.5, 67.8, 55.8, 53.8, 47.0, 46.1, 44.9, 39.2,
26.2, 24.6, 23.6, 20.6, 15.9; FAB MS m/z (M+ + H) calcd for
709.60; [R]20 -89.7 (c 1.38, CHCl3).
D
C
35H43O8 591.30, obsd 591.18; [R]20 -49.6 (c 0.66, CHCl3).
D
(1S,2R,5R,6S,7E)-6-[(2R,4S,5S)-5-(Ben zyloxy)-4-[2-(ter t-
b u t yld im et h ylsiloxy)et h yl]-2-p h en yl-m -d ioxa n -5-yl]-2-
(m eth oxym eth oxy)-5,11,11-tr im eth ylbicyclo[6.2.1]u n d ec-
7-en e-3,4-d ion e (54). Oxalyl chloride (0.81 mL of 0.68 M in
CH2Cl2, 0.56 mmol) was added to a solution of dimethyl
sulfoxide (0.81 mL of 1.38 M in CH2Cl2, 1.12 mmol) at -78
°C, followed 10 min later by a solution of 53 (132 mg, 0.19
mmol) in CH2Cl2 (1 mL). The mixture was stirred at -78 °C
for 1 h, at which point a solution of triethylamine (0.30 mL,
2.27 mmol) in CH2Cl2 (1 mL) was introduced. The mixture
was allowed to warm to 20 °C and diluted with ether and brine.
The separated organic layer was extracted with ether, and the
combined organic phases were dried, filtered, and concen-
trated. Chromatography of the residue on silica gel (elution
with18% ether in hexanes) gave 54 as a yellowish oil (108 mg,
82%): IR (film, cm-1) 1699; 1H NMR (300 MHz, CDCl3) δ 7.54-
7.22 (m, 10 H), 5.59 (s, 1 H), 5.43 (d, J ) 10.4 Hz, 1 H), 5.15
(d, J ) 11.6 Hz, 1 H), 5.08 (d, J ) 11.6 Hz, 1 H), 4.69 (s, 1 H),
4.67 (d, J ) 6.9 Hz, 1 H), 4.52 (d, J ) 13.0 Hz, 1 H), 4.47 (d,
J ) 6.8 Hz, 1 H), 4.38 (dd, J ) 9.9, 1.5 Hz, 1 H), 4.22 (d, J )
13.0 Hz, 1 H), 3.93-3.74 (m, 2 H), 3.38 (s, 3 H), 2.80 (t, J )
10.5 Hz, 1 H), 2.26-1.98 (m, 7 H), 1.75-1.65 (m, 1 H), 1.32
(d, J ) 3.3 Hz, 3 H), 1.20 (s, 3 H), 1.08 (s, 3 H), 0.92 (s, 9 H),
0.07 (s, 3 H), 0.06 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm
203.5, 201.2, 146.4, 139.6, 138.3, 128.9, 128.2 (2 C), 128.1 (2
C), 127.1 (2 C), 127.0, 126.2 (2 C), 123.6, 101.0, 95.8, 82.9, 78.9,
74.1, 71.0, 67.9, 58.7, 55.8, 53.9, 46.7, 45.9, 39.7, 32.5, 26.2,
26.0 (3 C), 24.6, 23.5, 20.7, 18.3, 15.7, -5.3, -5.5; FAB MS
(3R,4aR,6R,6aR,9R,10S,13E,14aS,14bS)-14b-(Ben zyloxy)-
4a,5,6,6a,9,10,11,12,14a,14b-decah ydr o-6-h ydr oxy-9-(m eth -
oxym eth oxy)-6a,15,15-tr im eth yl-3-ph en yl-10,13-m eth an o-
1H-cyclod eca [f][1,3]-ben zod ioxin -7,8-d ion e Aceta te (58).
To a solution of tetra-n-butylammonium fluoride (0.5 mL, 0.5
mmol) in acetonitrile (1.0 mL) was added a solution of 56 (10
mg, 0.017 mg, 0.017 mol) in acetonitrile. The resulting
solution was immediately diluted with ether, and the mixture
was washed with saturated NH4Cl solution. The aqueous
phase was extracted with ether, dried, and filtered. Solvent
evaporation furnished the aldol product as a yellow oil: IR
1
(film, cm-1) 3424, 1687; H NMR (300 MHz, CDCl3) δ 7.53-
7.27 (m, 10 H), 5.66 (s, 1 H), 5.42 (d, J ) 11.5 Hz, 1 H), 5.02
(ddd, J ) 12.1, 5.6, 4.1 Hz, 1 H), 4.81 (d, J ) 10.5 Hz, 1 H),
4.67 (d, J ) 6.8 Hz, 1 H), 4.66 (s, 1 H), 4.58 (d, J ) 10.5 Hz,
1 H), 4.44 (d, J ) 6.8 Hz, 1 H), 4.26 (dd, J ) 12.1, 3.9 Hz, 1
H), 4.22 (d, J ) 12.6 Hz, 1 H), 3.76 (d, J ) 12.7 Hz, 1 H), 3.38
(s, 3 H), 3.21 (d, J ) 11.6 Hz, 1 H), 2.69 (d, J ) 5.9 Hz, 1 H),
2.43 (q, J ) 12.1 Hz, 1 H), 2.31-2.18 (m, 4 H), 2.06 (dt, J )
11.8, 3.9 Hz, 1 H), 1.78-1.71 (m, 1 H), 1.46 (s, 3 H), 1.18 (s, 3
H), 1.10 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 204.1, 202.3,
152.0, 138.3, 137.8, 192.2, 128.4 (2 C), 128.2 (2 C), 127.7 (2
C), 127.3, 126.5 (2 C), 117.0, 102.3, 96.1, 84.2, 78.2, 71.9, 68.5,
67.1, 64.1, 58.0, 55.9, 55.2, 46.0, 44.2, 30.7, 26.2, 24.7, 24.0,
21.1, 16.0; FAB MS m/z (M+ + H) calcd for C35H43O8 591.30,
obsd 591.37; [R]20 +8.1 (c 0.37, CHCl3).
D
The unpurified aldol from above was dissolved in CH2Cl2
and treated with triethylamine (0.40 mL, 0.28 mmol), acetic
anhydride (0.021 mL, 0.14 mmol), and a catalytic amount of
DMAP. The mixture was stirred for 3 h and diluted with
CH2Cl2 and saturated NH4Cl solution. The separated aqueous
phase was extracted with CH2Cl2, and the combined organic
solutions were dried, filtered, and evaporated. The residue
was chromatographed on silica gel (elution with 25% ethyl
acetate in hexanes) to give 58 as a yellow oil (5 mg, 47% for 2
steps): IR (film, cm-1) 1742, 1693; 1H NMR (300 MHz, CDCl3)
δ 7.51-7.27 (m, 10 H), 6.08 (dd, J ) 11.7, 4.2 Hz, 1 H), 5.65
(s, 1 H), 5.41 (d, J ) 11.7 Hz, 1 H), 4.83 (d, J ) 10.4 Hz, 1 H),
4.65-4.56 (m, 3 H), 4.37 (d, J ) 6.9 Hz, 1 H), 4.33 (dd, J )
11.8, 4.0 Hz, 1 H), 4.22 (d, J ) 12.7 Hz, 1 H), 3.79 (d, J ) 12.8
Hz, 1 H), 3.35 (s, 3 H), 3.23 (d, J ) 11.6 Hz, 1 H), 2.43-2.13
(m, 6 H), 1.91 (s, 3 H), 1.76-1.65 (m, 1 H), 1.53 (s, 3 H), 1.18
(s, 3 H), 1.08 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 203.0,
199.7, 169.9, 152.2, 138.3, 137.8, 129.2, 128.4 (2 C), 128.3 (2
C), 127.8 (2 C), 127.4, 126.4 (2 C), 117.3, 102.3, 95.9, 83.7, 77.1,
71.8, 70.9, 68.5, 64.3, 55.8, 55.2, 54.9, 46.2, 44.7, 27.5, 26.4,
24.7, 24.0, 21.1, 20.7, 17.6; FAB MS m/z (M+ + H) calcd for
m/z (M+ + H) calcd for C41H59O8Si 707.40, obsd 707.47; [R]20
-38.3 (c 2.65, CHCl3).
D
(1S,2R,5R,6S,7E)-6-[(2R,4S,5S)-5-(Ben zyloxy)-4-(2-h y-
dr oxyeth yl)-2-ph en yl-m-dioxan -5-yl]-2-(m eth oxym eth oxy)-
5,11,11-tr im eth ylbicyclo-[6.2.1]u n dec-7-en e-3,4-dion e (55).
To a solution of 54 (273 mg, 0.39 mmol) in acetonitrile (10 mL)
at 0 °C was added 1.0 mL of hydrogen fluoride-pyridine. The
mixture was stirred at 0 °C for 15 min, quenched with solid
NaHCO3, and diluted with water and ether. The separated
aqueous phase was extracted with ether, and the combined
organic solutions were dried, filtered, and chromatographed
on silica gel (elution with 50% ethyl acetate in hexanes) to
provide 55 as a yellow oil (185 mg, 85%): IR (film, cm-1) 3440,
1698; 1H NMR (300 MHz, CDCl3) δ 7.52-7.23 (m, 10 H), 5.62
(s, 1 H), 5.42 (d, J ) 10.3 Hz, 1 H), 5.17 (d, J ) 11.3 Hz, 1 H),
5.02 (d, J ) 11.3 Hz, 1 H), 4.68 (d, J ) 6.6 Hz, 1 H), 4.66 (d,
J ) 11.8 Hz, 1 H), 4.63-4.39 (m, 3 H), 4.12 (d, J ) 13.1 Hz, 1
H), 3.94-3.81 (m, 3 H), 3.36 (s, 3 H), 2.73 (t, J ) 10.6 Hz, 1
H), 2.30-1.93 (m, 7 H), 1.74-1.67 (m, 1 H), 1.28 (d, J ) 6.6
Hz, 3 H), 1.20 (s, 3 H), 1.08 (s, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 203.6, 201.5, 147.2, 139.2, 137.9, 129.1, 128.4 (2 C), 128.2
(2 C), 127.22 (2 C), 127.17, 126.1 (2 C), 123.2, 101.0, 95.8, 82.8,
81.4, 73.9, 71.4, 67.7, 60.1, 55.8, 53.8, 46.7, 46.0, 39.8, 32.6,
C
37H45O9 633.31, obsd 633.23; [R]20 +21.6 (c 0.19, CHCl3).
D
Eth yl 2-C-(Hyd r oxym eth yl)-3-O-(p-m eth oxyben zyl)-D-
a r a bin ofu r a n osid e (59). Diol 15 (10.0 g, 27.1 mmol) and
pyridinium p-toluenesulfonate (354 mg, 1.41 mmol) in ethanol

C Ring Construction via Intramolecular Aldolization
J . Org. Chem., Vol. 63, No. 23, 1998 8507
(150 mL) were refluxed for 4 h and cooled to rt. The solvent
was evaporated, and the residue was purified by chromatog-
raphy on silica gel (elution with 60% ethyl acetate in hexanes)
to furnish 59 (7.43 g, 83%) as an oily mixture of anomers.
r-An om er : IR (film, cm-1) 3444, 1614; 1H NMR (300 MHz,
CDCl3) δ 7.24 (d, J ) 8.7 Hz, 2 H), 6.87 (d, J ) 8.7 Hz, 2 H),
4.93 (s, 1 H), 4.70 (d, J ) 11.3 Hz, 1 H), 4.51 (d, J ) 11.3 Hz,
1 H), 4.10 (d, J ) 6.6 Hz, 1 H), 3.99-3.95 (m, 1 H), 3.96 (d, J
) 12.1 Hz, 1 H), 3.87 (dq, J ) 9.8, 7.1 Hz, 1 H), 3.79 (s, 3H),
3.72-3.68 (m, 1 H), 3.69 (d, J ) 12.1 Hz, 1 H), 3.62 (dq, J )
9.8, 7.1 Hz, 1 H), 3.52 (dd, J ) 11.9, 4.3 Hz, 1 H), 2.51 (br s,
3 H), 1.25 (t, J ) 7.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm
159.4, 129.6, 129.4 (2 C), 113.9 (2 C), 102.9, 83.3, 82.2, 81.4,
(107 mg, 4.45 mmol) was added in several portions to a solution
of 61 (971 mg, 2.23 mmol) and 2-(trimethylsilyl)ethoxymethyl
chloride (985 µL, 5.56 mmol) in THF (20 mL). The mixture
was stirred for 40 min in advance of the careful addition of
water. The reaction mixture was extracted with ether, and
the combined organic layers were dried in the presence of
triethylamine. The ethereal solution was concentrated to a
total volume of 10 mL, treated with triethylamine, filtered
through silica gel, treated again with triethylamine, and finally
fully concentrated and chromatographed (silica gel, elution
with 5% ethyl acetate in hexanes) to furnish the SEM
derivatives as a colorless oil (1.00 g, 80%).
r-An om er : IR (film, cm-1) 1615; 1H NMR (300 MHz, C6D6)
δ 7.56 (d, J ) 8.7 Hz, 2 H), 6.81 (d, J ) 8.7 Hz, 2 H), 5.60 (s,
1 H), 5.41 (s, 1 H), 4.64 (d, J ) 7.7 Hz, 1 H), 4.61 (d, J ) 7.7
Hz, 1 H), 4.54 (d, J ) 12.1 Hz, 1 H), 4.45 (ddd, J ) 6.7, 6.7,
3.2 Hz, 1 H), 4.18 (d, J ) 3.2 Hz, 1 H), 4.06 (d, J ) 12.1 Hz, 1
H), 3.77 (dq, J ) 9.6, 7.0 Hz, 1 H), 3.63 (ddd, J ) 8.5, 8.5, 1.4
Hz, 2 H), 3.31 (dq, J ) 9.6, 7.0 Hz, 1 H), 3.25 (s, 3 H), 3.21
(dd, J ) 7.0, 2.0 Hz, 2 H), 1.09 (t, J ) 7.0 Hz, 3 H), 0.93 (dd,
J ) 8.8, 7.8 Hz, 2 H), -0.0090 (s, 9 H); 13C NMR (75 MHz,
C6D6) ppm 160.6, 131.6, 127.8 (2 C), 113.8 (2 C), 107.1, 98.4,
90.8, 84.6, 83.7, 82.0, 66.0, 64.9, 63.8, 54.7, 18.2, 15.2, 6.12,
72.7, 65.1, 63.2, 62.4, 55.3, 15.2; [R]20 -8.52 (c 1.59, CHCl3).
D
1
â-An om er : H NMR (300 MHz, CDCl3) δ 7.25 (d, J ) 8.5
Hz, 2 H), 6.87 (d, J ) 8.5 Hz, 2 H), 4.87 (s, 1 H), 4.62 (d, J )
11.8 Hz, 1 H), 4.52 (d, J ) 11.8 Hz, 1 H), 4.13 (ddd, J ) 4.7,
2.7, 2.7 Hz, 1 H), 3.93 (d, J ) 12.0 Hz, 1 H), 3.88 (d, J ) 12.0
Hz, 1 H), 3.79 (s, 3 H), 3.83-3.72 (series of m, 3 H), 3.50 (dq,
J ) 9.8, 7.0 Hz, 1 H), 3.45 (dd, J ) 11.9, 2.8 Hz, 1 H), 2.81 (br
s, 3 H), 1.20 (t, J ) 7.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 159.4, 129.9, 129.5 (2 C), 113.9 (2 C), 108.3, 83.8, 82.9,
82.6, 72.7, 63.7, 62.2, 61.4, 55.3, 15.1; HRMS (EI) m/z (M+)
calcd for C16H24O7 328.1522, obsd 328.1511; [R]20 +90.0 (c
-1.34; [R]20 +58.2 (c 1.31, CHCl3).
D
D
0.66, CHCl3).
â-An om er : 1H NMR (300 MHz, C6D6) δ 7.49 (d, J ) 8.7
Hz, 2 H), 6.81 (d, J ) 8.7 Hz, 2 H), 5.60 (s, 1 H), 5.35 (s, 1 H),
5.16 (d, J ) 7.5 Hz, 1 H), 4.73 (d, J ) 7.5 Hz, 1 H), 4.46 (dd,
J ) 9.9, 6.0 Hz, 1 H), 4.41 (d, J ) 11.7 Hz, 1 H), 4.38 (s, 1 H),
4.26 (d, J ) 11.7 Hz, 1 H), 3.87-3.72 (series of m, 2 H), 3.57
(dd, J ) 9.7, 9.7 Hz, 1 H), 3.52-3.44 (m, 1 H), 3.32 (dd, J )
9.5, 5.9 Hz, 1 H), 3.26 (s, 3 H), 3.31-3.23 (m, 1 H), 0.98 (t, J
) 7.1 Hz, 3 H), 0.95-0.92 (m, 2 H), 0.011 (s, 9 H); 13C NMR
(75 MHz, C6D6) ppm 160.9, 130.9, 128.0 (2 C), 114.1 (2 C),
106.8, 100.2, 92.2, 84.8, 84.1, 76.1, 67.2, 66.6, 66.1, 55.0, 18.6,
15.7, 6.78, -0.99 (3 C); HRMS m/z (M+) calcd for C22H35IO7Si
Anal. Calcd for C16H24O7: C, 58.53; H, 7.37. Found: C,
58.27; H, 7.31.
(2S,4a S,7S,7a R)-5-Eth oxyd ih yd r o-7-(iod om eth yl)-2-(p-
m eth oxyp h en yl)-4H-fu r o[3,4-d ]-m -d ioxin -4a (5H)-ol (61).
A mixture of 59 (7.10 g, 21.6 mmol) and 3 Å molecular sieves
in CH2Cl2 (250 mL) at rt was treated with DDQ (9.82 g, 43.2
mmol) in three portions separated by 15 min intervals. The
murky mixture was stirred for 5 h and filtered through Celite
into saturated NaHCO3 and Na2S2O7 solutions. The organic
layer was separated, dried, and concentrated to leave a crude
solid, which was purified (chromatography on silica gel, elution
with 50% ethyl acetate in hexanes) to yield unreacted 59 (0.96
g, 14%) together with 60 (4.31 g, 61%) as a white amorphous
solid, which was used immediately in the next step.
Diol 60 (8.26 g, 25.3 mmol) was warmed (90 °C) with
imidazole (6.03 g, 88.6 mmol) and triphenylphosphine (16.6
g, 63.3 mmol) in a 4:1 toluene-acetonitrile (300 mL) solution.
Iodine (15.4 g, 60.6 mmol) was added in two portions, and the
mixture was stirred for 1 h prior to cooling and removal of
the solvent in vacuo. The residue was partitioned between
water and ether, and the latter was recovered, dried, and
concentrated to provide a yellow oil, which was purified by
silica gel chromatography (elution with 10-25% ethyl acetate
in hexanes) to provide R-61 (2.95 g, 27%) and â-61 (7.83 g,
71%) as colorless oils.
566.1197, obsd 566.1205; [R]20 -83.9 (c 0.93, CHCl3).
D
Anal. Calcd for C22H35IO7Si: C, 46.64; H, 6.23. Found: C,
46.71; H, 6.18.
A solution of iodide anomers (557 mg, 0.98 mmol) in 95%
ethanol (15 mL) containing pyridine (0.5 mL) was treated with
zinc dust (3.05 g, 46.6 mmol) and heated at 80-90 °C for 5 h.
The mixture was cooled, concentrated in vacuo, filtered
through Celite (ether wash), concentrated, and chromato-
graphed (silica gel, elution with 5% ethyl acetate in hexanes)
to provide 62 as a colorless oil (291 mg, 75%): IR (film, cm-1
)
1732, 1616; 1H NMR (300 MHz, C6D6) δ 10.1 (s, 1 H), 7.49 (d,
J ) 8.7 Hz, 2 H), 6.80 (d, J ) 8.7 Hz, 2 H), 6.24 (ddd, J )
17.3, 11.0, 4.0 Hz, 1 H), 5.55 (ddd, J ) 17.4, 1.8, 1.8 Hz, 1 H),
5.41 (s, 1 H), 5.16 (ddd, J ) 10.9, 1.8, 1.8 Hz, 1 H), 4.74 (d, J
) 7.6 Hz, 1 H), 4.65 (d, J ) 11.3 Hz, 1 H), 4.57 (d, J ) 7.6 Hz,
1 H), 4.30 (ddd, J ) 3.8, 1.8, 1.8 Hz, 1 H), 3.78 (d, J ) 11.3
Hz, 1 H), 3.64 (ddd, J ) 9.4, 9.4, 7.1 Hz, 1 H), 3.44 (ddd, J )
9.4, 9.4, 7.1 Hz, 1 H), 3.26 (s, 3 H), 0.87-0.82 (m, 2 H), -0.033
(s, 9 H); 13C NMR (75 MHz, C6D6) ppm 200.5, 160.7, 131.9,
130.5, 128.2 (2 C), 117.5, 113.9 (2 C), 102.0, 91.5, 81.6, 75.7,
71.0, 65.9, 54.8, 18.2, -1.41 (3 C); HRMS m/z (M+) calcd for
r-An om er : IR (film, cm-1) 3460, 1684, 1614; 1H NMR (300
MHz, CDCl3) δ 7.41 (d, J ) 8.7 Hz, 2 H), 6.89 (d, J ) 8.7 Hz,
2 H), 5.51 (s, 1 H), 5.03 (s, 1 H), 4.38 (d, J ) 12.0 Hz, 1 H),
4.28 (ddd, J ) 5.3, 5.3, 3.0 Hz, 1 H), 3.94 (d, J ) 2.8 Hz, 1 H),
3.85 (d, J ) 12.0 Hz, 1 H), 3.86-3.81 (m, 1 H), 3.80 (s, 3H),
3.56 (dq, J ) 7.0, 7.0 Hz, 1 H), 3.51 (dd, J ) 10.6, 5.8 Hz, 1
H), 3.43 (dd, J ) 10.6, 4.9 Hz, 1 H), 2.49 (br s, 1 H), 1.27 (t, J
) 7.0 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 160.0, 130.1,
127.6 (2 C), 113.6 (2 C), 109.0, 98.3, 84.9, 83.0, 82.9, 67.3, 63.5,
C
20H30O6Si 394.1812, obsd 394.1792; [R]20 -24.2 (c 0.38,
D
CHCl3).
[2-[[[(2S,4R,5S)-5-[(Z)-2-Iodovin yl]-2-(p-m eth oxyph en yl)-
55.2, 15.0, 7.38; [R]20 +89.1 (c 1.42, CHCl3).
4-vin yl-m -d ioxa n -5-yl]oxy]m e t h oxy]e t h yl]t r im e t h yl-
sila n e (63). A suspension of (iodomethyl)triphenylphospho-
nium iodide (2.53 g, 4.78 mmol) in THF (45 mL) was stirred
at rt while sodium hexamethyldisilazide (4.78 mL of 1 M in
THF) was added dropwise. The clear red solution was stirred
at rt for 10 min and cooled to 0 °C prior to addition via cannula
of a solution of 62 (1.25 g, 3.18 mmol) in THF (15 mL). The
cloudy red mixture was immediately warmed to rt, stirred for
an additional 15 min, diluted with water, and extracted with
ether. The ethereal layers were combined, dried, and concen-
trated before chromatography on silica gel (elution with 3%
ethyl acetate in hexanes) to yield 63 as a colorless oil (1.18 g,
D
â-An om er : 1H NMR (300 MHz, C6D6) δ 7.47 (d, J ) 8.7 Hz,
2 H), 6.80 (d, J ) 8.8 Hz, 2 H), 5.45 (s, 1 H), 5.19 (s, 1 H), 4.46
(dd, J ) 9.6, 6.3 Hz, 1 H), 4.30 (s, 1 H), 3.84 (d, J ) 11.6 Hz,
1 H), 3.64 (d, J ) 11.6 Hz, 1 H), 3.71-3.61 (m, 1 H), 3.36 (dd,
J ) 9.7 Hz, 1 H), 3.26 (s, 3 H), 3.30-3.24 (m, 1 H), 3.20 (dd,
J ) 9.7, 6.3 Hz, 1 H), 3.01 (s, 1 H), 0.90 (t, J ) 7.1 Hz, 3 H);
13C NMR (75 MHz, C6D6) ppm 160.6, 130.5, 113.7 (2C), 104.8,
99.9, 86.0, 83.1, 71.4, 69.0, 65.9, 54.8, 15.2, 6.25; HRMS m/z
(M+) calcd for C16H21IO6 436.0383, obsd 436.0389; [R]20D +11.6
(c 1.71, CHCl3).
Anal. Calcd for C16H21IO6: C, 44.05; H, 4.85. Found: C,
43.93; H, 4.80.
1
72%): IR (film, cm-1) 1616; H NMR (300 MHz, C6D6) δ 7.53
[2-[[[(2S,4a S,7S,7a R)-5-Eth oxyd ih yd r o-7-(iod om eth yl)-
2-(p-m eth oxyp h en yl)-4H-fu r o[3,4-d ]-m -d ioxin -4a (5H)-yl]-
oxy]m eth oxy]eth yl]tr im eth ylsila n e (62). Sodium hydride
(d, J ) 8.7 Hz, 2 H), 6.84 (d, J ) 9.0 Hz, 1 H), 6.81 (d, J ) 8.7
Hz, 2 H), 6.48 (ddd, J ) 17.3, 10.9, 4.0 Hz, 1 H), 6.29 (d, J )
9.0 Hz, 1 H), 5.61 (ddd, J ) 17.3, 2.0, 2.0 Hz, 1 H), 5.43 (s, 1

8508 J . Org. Chem., Vol. 63, No. 23, 1998
Paquette et al.
H), 5.30 (ddd, J ) 10.9, 1.9, 1.9 Hz, 1 H), 4.82 (d, J ) 7.9 Hz,
1 H), 4.78 (d, J ) 7.9 Hz, 1 H), 4.58 (d, J ) 11.0 Hz, 1 H),
4.38-4.36 (m, 1 H), 3.94 (d, J ) 11.0 Hz, 1 H), 3.81 (ddd, J )
9.6, 9.6, 6.4 Hz, 1 H), 3.50 (ddd, J ) 9.4, 9.4, 7.1 Hz, 1 H),
3.27 (s, 3 H), 0.96-0.89 (m, 2 H), -0.0069 (s, 9 H); 13C NMR
(75 MHz, C6D6) ppm 160.6, 136.9, 133.4, 130.9, 128.0 (2 C),
117.3, 113.8 (2 C), 101.7, 91.8, 83.6, 80.2, 75.8, 73.9, 66.0, 54.7,
18.3, -1.33 (3 C); HRMS m/z (M+) calcd for C21H31IO5Si
94.8, 90.4, 85.6, 85.1, 76.2, 72.1, 65.2, 55.5, 55.2, 54.4, 47.8,
46.9, 45.2, 30.2, 26.7, 26.1, 23.1, 19.7 (2 C), 18.3, -1.40 (3 C);
FAB MS m/z (M+ + H) calcd for C35H55O8Si 631.37, obsd
631.34; [R]20 -70.0 (c 0.61, CHCl3).
D
(1S,2R,4S,5S,7S,8S)-7,8-Dih ydr oxy-2-(m eth oxym eth oxy)-
5-[(2S,4R,5S)-2-(p-m eth oxyp h en yl)-5-[[2-(tr im eth ylsilyl)-
eth oxy]m eth oxy]-4-vin yl-m -d ioxa n -5-yl]-4,11,11-tr im eth -
ylbicyclo[6.2.1]u n d eca n -3-on e (66). Osmium tetraoxide
(4.9 mg, 19 µmol) was added to a chilled (0 °C) solution of 65
(13 mg, 21 µmol) in pyridine (1 mL) and stirred for 2 h before
being quenched with saturated Na2S2O4 solution. Following
an additional 2 h period of stirring at rt, the mixture was
extracted with ether, and the ethereal layers were dried and
concentrated to provide a residue, which was subjected to flash
chromatography (silica gel, elution with 30% ethyl acetate in
hexanes). There was isolated 66 (5.2 mg, 41%) and some
unreacted 65.
518.0986, obsd 518.0951; [R]20 +31.6 (c 0.89, CHCl3).
D
Anal. Calcd for C21H31IO5Si: C, 48.65; H, 6.03. Found: C,
48.93; H, 6.04.
(1S,2S,3R,4S)-3-(Meth oxym eth oxy)-2-[(Z)-2-[(2S,4R,5S)-
2-(p -m e t h o x y p h e n y l)-5-[[2-(t r im e t h y ls ily l)e t h o x y ]-
m et h oxy]-4-vin yl-m -d ioxa n -5-yl]vin yl]-7,7-d im et h yl-1-
vin ylbicyclo[2.2.1]h eptan -2-ol (64). A cold (-78 °C) solution
of 63 (685 mg, 1.32 mmol) in dry ether (15 mL) was treated
with n-butyllithium (0.90 of 1.6 M in pentane, 1.44 mmol) and
stirred for 5 min prior to the addition of 22 (269 mg, 1.20 mmol)
in ether (5 mL). The reaction mixture was stirred for 20 min,
quenched with water, warmed to rt, and diluted with ether.
Following separation of the biphasic mixture, the organic layer
was dried and concentrated to give an oil that was chromato-
graphed (silica gel, elution with 15% ethyl acetate in hexanes)
1
66: colorless oil; IR (film, cm-1) 3384, 1698, 1615; H NMR
(300 MHz, CDCl3) δ 7.43 (d, J ) 8.7 Hz, 2 H), 6.89 (d, J ) 8.7
Hz, 2 H), 6.32 (ddd, J ) 17.6, 11.0, 2.6 Hz, 1 H), 5.65 (s, 1 H),
5.56 (ddd, J ) 17.6, 1.7, 1.7 Hz, 1 H), 5.38 (ddd, J ) 11.0, 2.1,
2.1 Hz, 1 H), 4.91 (d, J ) 8.1 Hz, 1 H), 4.85 (d, J ) 8.1 Hz, 1
H), 4.72 (ddd, J ) 2.6, 1.9, 1.9 Hz, 1 H), 4.48 (d, J ) 6.9 Hz,
1 H), 4.32 (d, J ) 11.9 Hz, 1 H), 4.31 (d, J ) 6.9 Hz, 1 H), 4.22
(s, 1 H), 4.19 (d, J ) 11.9 Hz, 1 H), 3.82 (s, 3 H), 3.71 (dd, J )
8.4 Hz, 2 H), 3.42 (br d, J ) 11.4 Hz, 1 H), 3.23 (s, 3H), 3.18
(s, 1 H), 2.95 (q, J ) 6.4 Hz, 1 H), 2.77 (d, J ) 13.1 Hz, 1 H),
2.45-2.26 (series of m, 4 H), 2.04 (ddd, J ) 12.6, 12.6, 2.4 Hz,
1 H), 1.85 (dd, J ) 13.1, 13.1, 1.2 Hz, 1 H), 1.80-1.66 (series
of m, 2 H), 1.29 (d, J ) 6.4 Hz, 3 H), 1.05 (s, 3 H), 0.98 (s, 3
H), 0.96 (dd, J ) 8.4 Hz, 2 H), 0.043 (s, 9 H); 13C NMR (75
MHz, CDCl3) ppm 212.2, 160.0, 132.5, 129.8, 127.3 (2 C), 116.3,
113.5 (2 C), 101.5, 94.9, 89.4, 86.5, 82.5, 81.2, 75.5, 70.0, 69.0,
66.3, 55.9, 55.6, 55.3, 50.4, 47.6, 34.4, 32.7, 32.1, 29.8, 27.8,
18.2, 16.3, 10.4, -1.42 (3 C); FAB MS m/z (M+ + H) calcd for
to provide 64 as a colorless oil (564 mg, 76%): IR (film, cm-1
)
1
3400; H NMR (300 MHz, CDCl3) δ 7.41 (d, J ) 8.7 Hz, 2 H),
6.88 (d, J ) 8.7 Hz, 2 H), 6.06 (dd, J ) 17.7, 11.0 Hz, 1 H),
5.95 (ddd, J ) 17.4, 10.9, 4.4 Hz, 1 H), 5.81 (d, J ) 14.0 Hz, 1
H), 5.65 (d, J ) 14.0 Hz, 1 H), 5.55 (s, 1 H), 5.46 (ddd, J )
17.4, 1.7, 1.7 Hz, 1 H), 5.28 (s, 1 H), 5.28 (ddd, J ) 10.9, 1.7,
1.7 Hz, 1 H), 5.18 (dd, J ) 11.0, 2.0 Hz, 1 H), 4.98 (dd, J )
17.7, 2.0 Hz, 1 H), 4.95 (d, J ) 8.0 Hz, 1 H), 4.87 (d, J ) 8.0
Hz, 1 H), 4.71 (d, J ) 6.5 Hz, 1 H), 4.68 (d, J ) 6.5 Hz, 1 H),
4.62 (ddd, J ) 4.4, 1.8, 1.8 Hz, 1 H), 4.36 (d, J ) 10.3 Hz, 1
H), 4.11 (d, J ) 10.3 Hz, 1 H), 3.80 (s, 3 H), 3.78-3.63 (series
of m, 3 H), 3.37 (s, 3 H), 1.94 (d, J ) 5.0 Hz, 1 H), 1.80 (dddd,
J ) 12.4, 12.4, 3.4, 3.4 Hz, 1 H), 1.65 (ddd, J ) 13.1, 13.1, 4.7
Hz, 1 H), 1.51-1.42 (m, 1 H), 1.38 (s, 3 H), 1.17-1.09 (m, 1
H), 0.96 (dd, J ) 8.5, 8.5 Hz, 2 H), 0.78 (s, 3 H), 0.046 (s, 9 H);
13C NMR (75 MHz, CDCl3) ppm 160.1, 138.5, 136.0, 133.2,
130.1, 127.6 (2 C), 126.8, 118.2, 116.3, 113.6 (2 C), 101.4, 96.6,
90.0 (2 C), 84.0, 80.0, 74.1, 73.7, 66.7, 60.9, 55.4, 55.3, 50.83,
50.78, 25.9, 24.3, 22.1, 21.9, 18.1, -1.40 (3 C); HRMS m/z (M+)
C
35H57O10Si 665.37, obsd 665.38; [R]20 +17.8 (c 0.41, CHCl3).
D
(1S ,2R ,4S ,5S ,7S ,8S )-7-(t er t -Bu t yld im e t h ylsiloxy)-8-
h yd r oxy-2-(m et h oxym et h oxy)-5-[(2S,4R,5S)-2-(p -m et h -
oxyph en yl)-5-[[2-(tr im eth ylsilyl)eth oxy]m eth oxy]-4-vin yl-
m -d ioxa n -5-yl]-4,11,11-tr im eth ylbicyclo[6.2.1]u n d eca n -3-
on e (67). A solution of 66 (27 mg, 41 µmol), tert-butyldi-
methylsilyl chloride (12 mg, 82 µmol), imidazole (14 mg, 200
µmol), and a catalytic amount of 4-(N,N-dimethylamino)-
pyridine in DMF (0.2 mL) was stirred at rt for 12 h. An
additional 2.6 equiv of TBDMSCl and imidazole were next
added, and stirring was continued for 2 days. Water was
introduced, the mixture was extracted with ether, the organic
layers were dried and concentrated, and the residue was
chromatographed on silica gel (elution with 15% ethyl acetate
in hexanes) to furnish 67 as a colorless oil (23 mg, 73%) and
5.0 mg (19%) of unreacted 66: IR (film, cm-1) 3460, 1698, 1615;
1H NMR (300 MHz, CDCl3) δ 7.43 (d, J ) 8.7 Hz, 2 H), 6.90
(d, J ) 8.7 Hz, 2 H), 6.34 (ddd, J ) 17.4, 11.0, 2.6 Hz, 1 H),
5.64 (s, 1 H), 5.57 (ddd, J ) 17.4, 1.7, 1.7 Hz, 1 H), 5.42 (ddd,
J ) 11.0, 1.8, 1.8 Hz, 1 H), 4.93 (d, J ) 8.1 Hz, 1 H), 4.86 (d,
J ) 8.1 Hz, 1 H), 4.70 (ddd, J ) 2.3, 2.3, 2.3 Hz, 1 H), 4.49 (d,
J ) 6.9 Hz, 1 H), 4.31 (d, J ) 6.9 Hz, 1 H), 4.28 (d, J ) 12.0
Hz, 1 H), 4.24 (s, 1 H), 4.19 (s, 1 H), 4.15 (d, J ) 12.0 Hz, 1 H),
3.82 (s, 3 H), 3.72 (dd, J ) 8.4, 8.4 Hz, 2 H), 3.57 (dd, J )
11.7, 2.4 Hz, 1 H), 3.25 (s, 3 H), 3.01 (qd, J ) 6.8, 0.6 Hz, 1 H),
2.77 (br d, J ) 12.9 Hz, 1 H), 2.47-2.40 (m, 1 H), 2.38 (br s,
1 H), 2.33-2.29 (m, 1 H), 1.98 (dd, J ) 13.8, 13.8 Hz, 1 H),
1.82-1.70 (m, 3 H), 1.32 (d, J ) 6.5 Hz, 3 H), 1.05 (s, 3 H),
0.96 (dd, J ) 9.7 Hz, 2 H), 0.94 (s, 3 H), 0.88 (s, 9 H), 0.16 (s,
3 H), 0.12 (s, 3 H), 0.043 (s, 9 H); 13C NMR (75 MHz, CDCl3)
ppm 212.5, 160.0, 132.4, 129.7, 127.4 (2 C), 116.5, 113.5 (2 C),
101.4, 94.8, 89.3, 86.6, 82.5, 81.2, 75.5, 70.8, 69.5, 66.2, 55.9,
55.6, 55.3, 50.4, 47.4, 34.4, 32.6, 32.3, 30.3, 27.8, 25.8 (2 C),
18.2, 18.1, 16.9, 10.7, -1.42 (3 C), -3.08, -4.76; HRMS m/z
calcd for C34H52O8Si 616.3431, obsd 616.3444; [R]20 -17.0 (c
D
0.92, CHCl3).
Anal. Calcd for C34H52O8Si: C, 66.20; H, 8.50. Found: C,
66.12; H, 8.54.
(1S,2R,4S,5S,7E)-2-(Meth oxym eth oxy)-5-[(2S,4R,5S)-2-
(p-Meth oxyph en yl)-5-[[2-(tr im eth ylsilyl)eth oxy]m eth oxy]-
4-vin yl-m -d ioxa n -5-yl]-4,11,11-t r im et h ylb icyclo[6.2.1]-
u n d ec-7-en -3-on e (65). A solution of 64 (214 mg, 347 µmol)
and 18-crown-6 (275 mg, 1.04 mmol) in dry tetrahydrofuran
(8 mL) was deoxygenated (Ar), cooled to -78 °C, and treated
with potassium hexamethyldisilazide (2.78 mL of 0.5 M in
toluene, 1.39 mmol). The solution was stirred at -78 °C for 1
h, warmed to -30 °C for 1 h, and treated with methyl iodide
(216 µL, 3.37 mmol). The cloudy mixture was stirred for an
additional 2 h before the addition of water, warming to rt, and
extraction with ether. The ethereal layers were dried and
concentrated to leave a crude oil, which was purified via silica
gel chromatography (elution with 15% ethyl acetate in hex-
anes) to furnish 65 as a colorless oil (115 mg, 53%): IR (film,
1
cm-1) 1709, 1615; H NMR (300 MHz, CDCl3) δ 7.42 (d, J )
8.7 Hz, 2 H), 6.87 (d, J ) 8.7 Hz, 2 H), 6.23 (ddd, J ) 17.3,
10.8, 4.6 Hz, 1 H), 5.58 (s, 1 H), 5.40 (d, J ) 8.2 Hz, 1 H), 5.37
(ddd, J ) 17.3, 1.7, 1.7 Hz, 1 H), 5.23 (dd, J ) 11.3, 3.8 Hz, 1
H), 5.17 (ddd, J ) 10.8, 1.7, 1.7 Hz, 1 H), 5.09 (d, J ) 11.2 Hz,
1 H), 4.64 (d, J ) 8.6 Hz, 1 H), 4.63 (d, J ) 6.8 Hz, 1 H), 4.44-
4.40 (m, 2 H), 4.38 (d, J ) 6.8 Hz, 1 H), 4.07 (d, J ) 1.6 Hz, 1
H), 3.91 (ddd, J ) 11.1, 9.6, 5.7 Hz, 1 H), 3.79 (s, 3 H), 3.57
(ddd, J ) 11.1, 9.7, 6.3 Hz, 1 H), 3.30 (s, 3H), 2.73 (dd, J )
7.6, 2.1 Hz, 1 H), 2.61-2.32 (series of m, 4 H), 2.20-2.09 (series
of m, 3 H), 1.56 (ddd, J ) 14.1, 9.6, 4.8 Hz, 1 H), 1.36 (d, J )
7.8 Hz, 3 H), 1.17 (s, 3 H), 1.05 (s, 3 H), 1.03-0.88 (m, 2 H),
0.050 (s, 9 H); 13C NMR (75 MHz, CDCl3) ppm 211.8, 159.8,
146.6, 134.5, 130.7, 127.5 (2 C), 124.3, 114.6, 113.5 (2 C), 101.5,
(M+) calcd for C41H70O10Si2 778.4508, obsd 778.4506; [R]20
+33.3 (c 0.27, CHCl3).
D
(1S ,2R ,4S ,5S ,7S ,8S )-7-(t er t -Bu t yld im e t h ylsiloxy)-8-
h yd r oxy-5-[(2S,4R,5S)-4-(2-h yd r oxyeth yl)-2-(p-m eth oxy-
p h en yl)-5-[[2-(tr im eth ylsilyl)eth oxy]m eth oxy]-m -d ioxa n -
5-yl]-2-(m eth oxym eth oxy)-4,11,11-tr im eth ylbicyclo[6.2.1]-

C Ring Construction via Intramolecular Aldolization
J . Org. Chem., Vol. 63, No. 23, 1998 8509
u n d eca n -3-on e (68). Thexylborane was prepared by com-
bining 2,3-dimethylbutene (0.15 mL, 1 M in THF) and borane-
tetrahydrofuran (0.15 mL, 1 M in THF) at 0 °C for 1.5 h. To
this solution was added 67 (30 mg, 39 µmol) in THF (0.6 mL),
and the resulting mixture was stirred for 30 min at 0 °C,
treated with aqueous KOH (1.5 mL of a 3 M soln) and 30%
H2O2 (1.5 mL), warmed to rt for 12 h, and extracted with ether.
The combined organic layers were dried and concentrated, and
the residue was purified via flash chromatography (silica gel,
elution with 30% ethyl acetate in hexanes) to furnish the
primary (12.7 mg, 41%) and secondary carbinols (6.3 mg, 21%),
both as colorless oils.
in hexanes) to give 9.8 mg (82%) 68 and unchanged alcohol
(2.2 mg, 18%), both as colorless oils.
68: IR (film, cm-1) 3464, 1731, 1701; 1H NMR (300 MHz,
CDCl3) δ 9.86 (s, 1 H), 7.36 (d, J ) 8.7 Hz, 2 H), 6.86 (d, J )
8.7 Hz, 2 H), 5.68 (s, 1 H), 4.81 (s, 2 H), 4.81 (d, J ) 11.7 Hz,
1 H), 4.51 (d, J ) 7.0 Hz, 1 H), 4.37 (d, J ) 7.0 Hz, 1 H), 4.33
(d, J ) 11.8 Hz, 1 H), 4.22 (s, 1H), 4.21 (d, J ) 8.9 Hz, 1 H),
4.18 (d, J ) 11.8 Hz, 1 H), 3.80 (s, 3 H), 3.68-3.57 (m, 3 H),
3.27 (s, 3 H), 3.08 (d, J ) 5.8 Hz, 2 H), 2.94 (q, J ) 6.4 Hz, 1
H), 2.98-2.88 (m, 1 H), 2.40 (d, J ) 10.9 Hz, 1 H), 2.36-2.22
(m, 2 H), 1.95-1.82 (m, 3 H), 1.70-1.62 (m, 1 H), 1.33 (d, J )
6.4 Hz, 3 H), 1.06 (s, 3 H), 0.97 (s, 3 H), 0.89 (s, 9 H), 0.95-
0.86 (m, 2 H), 0.17 (s, 3 H), 0.14 (s, 3 H), 0.026 (s, 9 H); 13C
NMR (75 MHz, CDCl3) ppm 211.9, 119.2, 160.0, 129.2, 127.2
(2 C), 113.5 (2 C), 102.0, 94.8, 89.3, 86.6, 82.3, 77.4, 74.2, 71.1,
70.9, 66.4, 55.7, 55.5, 55.3, 50.4, 48.3, 44.2, 33.4, 33.0, 32.4,
30.2, 28.0, 25.8 (3 C), 18.1 (2 C), 16.8, 10.5, -1.46 (3 C), -3.10,
-4.78; FAB MS m/z (M+ + H) calcd for C41H71O11Si2 795.45,
P r im a r y Ca r bin ol: IR (film, cm-1) 3464, 1699, 1616; 1H
NMR (300 MHz, CDCl3) δ 7.37 (d, J ) 8.7 Hz, 2 H), 6.87 (d, J
) 8.7 Hz, 2 H), 5.61 (s, 1 H), 4.90 (d, J ) 8.2 Hz, 1 H), 4.83 (d,
J ) 8.2 Hz, 1 H), 4.51 (d, J ) 7.0 Hz, 1 H), 4.39 (d, J ) 7.9 Hz,
1 H), 4.36 (d, J ) 7.0 Hz, 1 H), 4.25 (d, J ) 12.0 Hz, 1 H), 4.23
(s, 2 H), 4.03 (d, J ) 12.0 Hz, 1 H), 3.90-3.86 (m, 1 H), 3.80
(s, 3 H), 3.80-3.62 (series of m, 4 H), 3.26 (s, 3 H), 3.00 (q, J
) 6.7 Hz, 1 H), 2.89 (br d, J ) 12.6 Hz, 1 H), 2.44-2.28 (series
of m, 3 H), 2.20-1.66 (series of m, 7 H), 1.36 (d, J ) 6.7 Hz, 3
H), 1.07 (s, 3 H), 0.97 (s, 3 H), 0.89 (s, 9 H), 0.94-0.85 (m, 2
H), 0.17 (s, 3 H), 0.14 (s, 3 H), 0.035 (s, 9 H); 13C NMR (75
MHz, CDCl3) ppm 212.1, 160.0, 129.5, 127.3 (2 C), 113.6 (2
C), 102.0, 94.7, 88.9, 86.6, 82.3, 80.8, 74.7, 70.9, 70.4, 66.3,
60.3, 55.7, 55.6, 55.3, 50.4, 48.2, 33.7, 32.7, 32.2, 30.3, 28.1,
25.8 (3 C), 18.12, 18.09, 16.8, 10.8, -1.47 (3 C), -3.07, -4.78;
FAB MS m/z (M+ + H) calcd for C41H73O11Si2 797.47, obsd
obsd 795.63; [R]20 +17.7 (c 0.87, CHCl3).
D
Ack n ow led gm en t. We thank the National Cancer
Institute of the Public Health Service for research
support.
Su p p or tin g In for m a tion Ava ila ble: Copies of the high-
field 1H NMR spectra for all compounds reported herein (52
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
797.48; [R]20 +18.1 (c 1.27, CHCl3).
D
The Dess-Martin periodinane (9.6 mg, 23 µmol) was stirred
in CH2Cl2 (1 mL) with the primary carbinol (12 mg, 15 µmol)
for 1 h, concentrated to about 0.2 mL, transferred to a flash
column, and purified (silica gel, elution with 20% ethyl acetate
J O981749J